WO2005118578A1 - Mercaptoimidazoles as ccr2 receptor antagonists - Google Patents

Mercaptoimidazoles as ccr2 receptor antagonists Download PDF

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Publication number
WO2005118578A1
WO2005118578A1 PCT/EP2005/052369 EP2005052369W WO2005118578A1 WO 2005118578 A1 WO2005118578 A1 WO 2005118578A1 EP 2005052369 W EP2005052369 W EP 2005052369W WO 2005118578 A1 WO2005118578 A1 WO 2005118578A1
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WIPO (PCT)
Prior art keywords
formula
compound
mono
βalkyl
alkyl
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PCT/EP2005/052369
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French (fr)
Inventor
Gustaaf Maria Boeckx
Guy Rosalia Eugeen Van Lommen
Julien Georges Pierre-Olivier Doyon
Erwin Coesemans
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Janssen Pharmaceutica N.V.
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=34957884&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2005118578(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to BRPI0511599-0A priority Critical patent/BRPI0511599A/en
Priority to EP05755042A priority patent/EP1753758B1/en
Priority to EA200602193A priority patent/EA200602193A1/en
Priority to AU2005250156A priority patent/AU2005250156A1/en
Priority to MXPA06013764A priority patent/MXPA06013764A/en
Application filed by Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Priority to CA002566187A priority patent/CA2566187A1/en
Priority to US11/569,268 priority patent/US20070249691A1/en
Priority to JP2007513921A priority patent/JP2008500310A/en
Priority to DE602005013216T priority patent/DE602005013216D1/en
Priority to PA20058634401A priority patent/PA8634401A1/en
Publication of WO2005118578A1 publication Critical patent/WO2005118578A1/en
Priority to IL179518A priority patent/IL179518A0/en
Priority to NO20066011A priority patent/NO20066011L/en

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Definitions

  • the present invention concerns mercaptoimidazole derivatives having CCR2 receptor antagonistic properties.
  • the invention further relates to methods for their preparation and pharmaceutical compositions comprising them.
  • the invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of diseases mediated through activation of the CCR2 receptor, in particular the CCR2B receptor.
  • WO 02/066458 describes 2-thio-substituted imidazole derivatives having immunomodulating and/or inhibiting activity on the release of cytokines, especially TNF- ⁇ and IL- ⁇ .
  • FR 1,487,326 relates to tMo-imidazole derivatives useful as analgetic and for its vasodilatation activity.
  • FR 6,751 M describes io-imidazole derivatives as sedatives and analgesics.
  • US 3,850,944 describes 2-mercapto-5-(3- ⁇ yridyl)-imidazole derivatives having antiinflammatory activity.
  • Bull. Soc. Chim.Belg., 73, ppl81-188 (1964) describes the synthesis and properties of ⁇ -arylali lamines.
  • Archiv der Pharmazie, 305 (12), pp891-901 (1972) describes the synthesis and pharmacology of N-chloracyl-benzylamines.
  • Annales pharmaceutiques francaises, 29(1), pp 63-70 (1971) describes the synthesis of imidazole derivatives.
  • the compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity and/or pharmacological potency.
  • R 5 represents hydrogen, Ci- ⁇ alkyl, hydroxyCi-ealkyl, C 2- $alkenyl, C 2 - 6 alkynyl, aminoC ⁇ . 6 alkyl, mono-or aminocarbonylCi-6alkyl, mono-or di ⁇ i ⁇ alky ⁇ aminocarbonylCi- ⁇ alkyl or aryl;
  • R ⁇ a and R ⁇ b each independently represent hydrogen, C ⁇ aHcyl, amino, mono-or di(C ⁇ - 4 alkyl)amino, arylNH-, aminoCi- ⁇ alkyl, mono-or di(C ⁇ - 4 alkyl)amino- C ⁇ - 6 alkyl, aminocarbonylamino, Ci- ⁇ alkyloxy, carbonylamino or hydroxyC ⁇ - 6 alkyl; or
  • R ⁇ a and R ⁇ b taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomorpholinyl or piperazinyl substituted with C ⁇ alkyl;
  • R represents hydrogen, hydroxyCi- ⁇ alkyL C 2 - 6 alkenyl, C 2-6 alkynyl, polyhaloCi- ⁇ alkyl, aminoCi- ⁇ alkyl, mono-or di(C 1- al ⁇ l)aminoC ⁇ alkyl, aminocarbonylCi- ⁇ alkyl, mono-or d ⁇ Ci-Aalky ⁇ aminocarbonylCi-ealkyl, aryl or heteroaryl;
  • Z represents a cyclic ring system selected from
  • each Rg independently represents hydrogen, halo, polyhaloCi- ⁇ alkyl, polyhaloCi- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(C ⁇ - 4 alkyl)aminocarbonyI, amino, mono-or di(C ⁇ - 4 alkyl)amino, hydroxyCi- ⁇ alkylamino, aryl, aryloxy, piperidinyl, piperidmylamino, morpholinyl, piperazinyl or nitro; each R 9 independently represents hydrogen, halo or Ci- ⁇ alkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, polyhaloCi-galkyl, polyhaloCi-ealkyloxy, cyano, aminocarbonyl, mono-or di(Ci-4alkyl)aminocarbonyl, amino, mono-or
  • the present invention also relates to the use of a compound for the manufacture of a medicament for preventing or treating diseases mediated through activation of the
  • Ri represents hydrogen, C h alky!, C 3-7 cycloalkyl, di(C ⁇ - 6 alkyl)aminoC 1 ⁇ alkyl, aryl or heteroaryl; each R 2 independently represents halo, Ci- ⁇ alkyl, Ci- ⁇ alkyloxy, polyhaloCi- ⁇ alkyl, polyhaloCi- ⁇ alkyloxy, cyano, aminocarbonyl, amino, mono-or di(C ⁇ -4a ⁇ kyl)amino, nitro, aryl or aryloxy;
  • R» represents hydrogen or Ci- ⁇ alkyl;
  • 5 represents hydrogen, Ci- ⁇ alkyl, hydroxyCi-ealkyl, C 2 ⁇ alkenyl, C ⁇ alkynyl, aminoC ⁇ .
  • Rg a and R «, each independently represent hydrogen, Ci- ⁇ alkyl, amino, mono-or difC alky amino, arylN ⁇ -, aminoCi-ealkyl, mono-or di(C ⁇ -4alkyl)amino Ci- ⁇ alkyl, aminocarbonylamino, G- ⁇ alkyloxy, carbonylamino or hydroxyC ⁇ - 6 alkyl; or ⁇ a and R ⁇ , taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl or piperazinyl substituted with Ci- ⁇
  • R 7 represents hydrogen, Ci-ealkyl, hydroxyCi- ⁇ alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, polyhaloCi- ⁇ alkyl, Ci-salkyloxyG-ealkyl, aminoCi-ealkyl, mono-or aminocarbonylCi- ⁇ alkyl, mono-or d ⁇ C t -i t alky ⁇ aminocarbonylCi- ⁇ alkyl, aryl or heteroaryl;
  • Z represents a cyclic ring system selected from
  • each Rg independently represents hydrogen, halo, G- ⁇ alkyloxy, polyhaloCi-ealkyl, polyhaloC ⁇ - 6 alkyloxy, cyano, aminocarbonyl, mono-or amino, mono-or di(C ⁇ -4alkyl)amino, hydroxyC ⁇ - 6 alkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, mo ⁇ holinyl, piperazinyl or nitro; each R 9 independently represents hydrogen, halo or Ci- ⁇ alkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C h alky!, polyhaloCi- ⁇ alkyl, polyhaloG- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(C ⁇ -4a ] kyl)aminocarbonyl, amino, mono-or di
  • the present invention also relates to the use of a compound for the manufacture of a medicament for preventing or treating diseases mediated through activation of the CCR2 receptor, in particular for preventing or treating inflammatory diseases, wherein said compound is a compound of formula (I)
  • Ri represents hydrogen, Ci- ⁇ alkyl, C 3-7 cycloalkyl, di G- ⁇ alkylJaminoCi- ⁇ alkyl, aryl or heteroaryl; each R 2 independently represents halo, G- ⁇ alkyl, C ⁇ _ 6 alkyloxy, Ci- ⁇ alkylthio, polyhaloCi-ealkyloxy, cyano, aminocarbonyl, amino, mono-or di(C ⁇ -4alkyl)amino, nitro, aryl or aryloxy;
  • R-i represents hydrogen or G- ⁇ alkyl;
  • R 5 represents hydrogen, C ⁇ alkyl, hydroxyC ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyL, polyhaloC ⁇ - 6 alkyI, Ci-ealkyloxyCi- ⁇ alkyl, aminod- ⁇ alkyl, mono-or d ⁇ Ci ⁇ alky ⁇ aminocarbonylCi-ealkyl or aryl;
  • R ⁇ a and R ⁇ b each independently represent hydrogen, Ci- ⁇ alkyl, amino, mono-or di(G-4alkyl)amino, arylNH-, aminoCi- ⁇ alkyl, mono-or di(C ⁇ -4alkyl)amino C ⁇ - 6 alkylcarbonylamino, aminocarbonylamino, C ⁇ - 6
  • R ⁇ a and R ⁇ b taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl or piperazinyl substituted with G- ⁇ alkyl;
  • R 7 represents hydrogen, G-ealkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, aminoCi- ⁇ alkyl, mono-or di(C ⁇ -4a ⁇ kyl)aminoC ⁇ - 6 alkyl, aminocarbonylCi- ⁇ alkyl, mono-or d ⁇ C alky ⁇ aminocarbonylCi- ⁇ alkyl, aryl or heteroaryl;
  • Z represents a cyclic ring system selected from
  • each Rg independently represents hydrogen, halo, Chalky 1, G- ⁇ alkyloxy, polyhalod- ⁇ alkyl, polyhaloCi- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(Ci-4alkyl)aminocarbonyl, amino, mono-or hydroxyCi- ⁇ alkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, mo ⁇ holinyl, piperazinyl or nitro; each R 9 independently represents hydrogen, halo or G- ⁇ alkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C h alky., Cj- ⁇ alkyloxy, polyhaloC ⁇ alkyl, polyhaloG- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(C ⁇ -4alkyl)amin
  • a particular embodiment of the present invention are those compounds of formula (I) as defined hereinabove or hereinafter provided that l-(3,4-dimethoxybenzyl)-4-phenyl- lH-imidazole-2-thiol; l-(o-chlorobenzyl)-5-e yl-4-phenyl-imidazole-2-thiol or pharmaceutically acceptable addition salts thereof are not included.
  • a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl;
  • G ⁇ alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for C ⁇ -4alkyl and pentyl, hexyl, 2-methylbutyl and the like;
  • C 3-7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
  • C 2- ⁇ salkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like;
  • C ⁇ alkyl
  • halo is generic to fluoro, chloro, bromo and iodo.
  • polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl;
  • polyhaloC ⁇ - 6 alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C h alky!, for example, the groups defined in polyhalomethyl, 1,1-difluoro-ethyl and the like.
  • more than one halogen atoms are attached to an alkyl group within the definition of polyhalomethyl or they may be the same or different.
  • heteroaryl in the definition of Ri or R 7 is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises lH-pyrrolyl and 2H-pyrrolyl.
  • aryl, heteroaryl, heterocyclic ring systems or cyclic ring systems listed in the definitions of the substituents of the compounds of formula (I) may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate, if not otherwise specified.
  • heteroaryl when heteroaryl is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.
  • Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.
  • the lines are drawn into bicyclic ring systems, it indicates that the bond may be attached to any of the suitable ring atoms of any one of the two cycles of the bicyclic ring system.
  • salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
  • the latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g.
  • hydrochloric, hydrobromic and the like sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy- acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfo ic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
  • the salt form can be converted by treatment with alkali into the free base form.
  • the compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • methylamine, ethylamine, propyla ine, isopropylamine such as methylamine, ethylamine, propyla ine, isopropylamine
  • the four bulylamine isomers dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n- butylamine, pyrrolidine, piperidine, mo ⁇ holine, trimethylamine, triethylamine, tripropylamine, quinucUdine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l, 3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the salt form can be converted by treatment with acid into the free acid form.
  • addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl7-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Counterions include chloro, bromo, iodo, trifluoroacetate and acetate.
  • the counterion of choice can be introduced using ion exchange resins.
  • N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
  • stereochemically isomeric forms as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines, polymo ⁇ hic forms or physiologically functional derivatives may possess.
  • chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates, quaternary amines or polymo ⁇ hic forms substantially free, i.e.
  • polymo ⁇ hic forms of the present compounds also fall within the ambit of the present invention.
  • the term "polymo ⁇ hic forms” as used hereinbefore or hereinafter defines all possible crystalline arrangement of a particular compound.
  • a polymo ⁇ hic form of a compound is the same chemical entity, but in a different crystalline arrangement.
  • the term "polymo ⁇ hic form” is well-known to a person skilled in the art.
  • Polymo ⁇ hic forms of pharmaceutical compounds may be of interest to those involved in the development of a suitable dosage form because if the polymo ⁇ hic form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next.
  • a pharmaceutical compound is produced for use, it is important to recognize the polymo ⁇ hic form delivered in each dosage form to assure that the production process use the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to assure that either a single polymo ⁇ hic form or some known combination of polymo ⁇ hic forms is present.
  • certain polymo ⁇ hic forms may exhibit enhanced thermodynamic stability and may be more suitable than other polymo ⁇ hic forms for inclusion in pharmaceutical formulations.
  • formula (I) includes the tautomeric form of NH being N .
  • the compounds of the present invention include compounds of formula (I)
  • R 5 represents hydrogen, G- ⁇ alkyl, hydroxyCi-ealkyl, C 2-6 alkenyL, C 2-6 alkynyl, polyhaloCi- ⁇ alkyl, Ci- ⁇ alkyloxyCi-ealkyl, aminoCi-ealkyl, mono-or aminocarbonylCi- ⁇ alkyl, mono-or difCi ⁇ alky ⁇ aminocarbonylCi-ealkyl or aryl; ⁇ a and R «b each independently represent hydrogen, amino, mono-or di(C ⁇ -4alkyl)amino, arylNH-, aminoC ⁇ -6alkyl, mono-or carbonylamino or hydroxyC ⁇ - 6 alkyl; or R ⁇ a and R ⁇ taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl or
  • each R « independently represents hydrogen, halo, G- ⁇ alkyloxy, poIyhaloCi- ⁇ alkyl, polyhaloG- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(Ci-4alkyl)aminocarbonyl, amino, mono-or hyoroxyC ⁇ alkylamino, aryl, aryloxy, piperidinyl, piperidmylamino, mo ⁇ holinyl, piperazinyl or nitro; each R 9 independently represents hydrogen, halo or C h alky]; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, G ⁇ alkyl, G-salkyloxy, polyhaloG- ⁇ alkyl, polyhaloG- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(C ⁇ -4alkyl)aminocarbon
  • R 5 represents hydrogen, C 2 _ 6 alkynyl, polyhaloC ⁇ - ⁇ alkyl, C ⁇ -6 alkyloxyC 1-6 alkyl, aminoCi- ⁇ alkyl, mono-or aminocarbonylCi-ealkyl, mono-or di(C ⁇ -4alkyl)aminocarbonylC ⁇ -6alkyl or aryl;
  • R ⁇ a and R ⁇ b each independently represent hydrogen, Ci- ⁇ alkyl, amino, mono-or di(C ⁇ -4alkyl)amino, arylNH-, aminoC ⁇ - 6 alkyl, mono-or cu(C ⁇ .4alkyl)arr ⁇ ino- G- ⁇ alkyl, Ci- ⁇ alkylcarbonylamino, aminocarbonylamino, G ⁇ alkyloxy, carbonylamino or hydroxyQ- ⁇ alkyl; or
  • R « a and R «, taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, mo ⁇ holinyl, thiomo ⁇ holinyl or piperazinyl substituted with C h alky!;
  • R 7 represents hydrogen, G ⁇ alkyl, hydroxyCi ⁇ alkyl, C 2 _$alkenyl, C 2 _ 6 alkynyl, polyhaloCi- ⁇ alkyl, Ci-ealkyloxyCi- ⁇ alkyl, aminoG-ealkyl, mono-or di(C ⁇ - 4 alkyl)aminoC ⁇ - 6 alkyl, mono-or d ⁇ C alky ⁇ aminocarbonylCi- ⁇ alkyl, aryl or heteroaryl;
  • each Rg independently represents hydrogen, halo, C h alky!, Ci- ⁇ alkyloxy, polyhaloG-ealkyl, polyhaloCi- ⁇ alkyloxy, cyano, aminocarbonyl, mono-or di(C ⁇ - 4 alkyl)aminocarbonyl, amino, mono-or di(C ⁇ - 4 alkyl)amino, hydroxyCi- ⁇ alkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, mo ⁇ holinyl, piperazinyl or nitro; each R 9 independently represents hydrogen, halo or G ⁇ alkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C h alky!, polyhaloCi-ealkyl, polyhaloQ- ⁇ alkyloxy, cyano, aminocarbonyl, mono-
  • a seventh interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Z is other than 3- pyridyl.
  • Z is a cyclic ring system selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-9), (a-10), (a-11), (a- 12), (a-13), (a- 14), (a- 15) or (a- 16) as defined hereinabove; preferably a cyclic ring system selected from (a-1), (a-2), (a-3), (a-4), (a-9), (a-10), (a- 12), (a- 13), (a- 14), (a- 16) or (a- 18); more preferably a cyclic ring system selected from (a-1), (a-2), (a-3), (a-9), (a-10), (a-12), (a-13),
  • a tenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein n is 2 or 3; preferably wherein n is 2.
  • An eleventh interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein n is 2 and said two R 2 substituents are placed in meta and para postion.
  • a twelfth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 2 represents halo, C h alky], G ⁇ alkyloxy or polyhaloG- ⁇ alkyl; preferably halo or polyhaloQ gally, in particular chloro, fluoro or trifluoromethyl; most preferred halo, in particular chloro or fluoro, more in particular fluoro.
  • a thirteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Ri is hydrogen, methyl, ethyl, n-propyl, methoxymethyl, cyclohexyl, cyclopropyl, dimethylaminomethyl, 2-thienyl, 3,4-dichlorophenyl; preferably Ri is or in particular methyl, ethyl, propyl, methoxymethyl, more in particular methyl, ethyl, n-propyl or methoxymethyl; more preferably Ri is G- 6 alkyl, in particular methyl, ethyl and propyl, more in particular methyl, ethyl or n-propyl; most preferred Ri is ethyl.
  • a fourteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein t is hydrogen.
  • a fifteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment which are stereochemically pure.
  • a sixteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the carbon atom carrying the Ri and t substituent has the (S) configuration, i.e. a compound of formula
  • N-oxide a pharmaceutically acceptable addition salt, a quaternary amine, a polymo ⁇ hic form or a stereochemically isomeric form thereof.
  • Ri represents C ⁇ _ 6 alkyl or Ci- alkyloxyCi-ealkyl, especially methyl, ethyl, propyl or methoxymethyl
  • R 2 represents halo, polyhaloCi- ⁇ alkyl or aryloxy, especially halo, e.g.
  • Z represents a ring system selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-9), (a-10), (a-11), (a- 12), (a-13), (a-14), (a-15) or (a-16);
  • R represents hydrogen; f) n is 2 or 3.
  • Ri represents especially methyl, ethyl, propyl or methoxymethyl
  • R 2 represents halo, especially chloro or fluoro
  • Z represents a ring system selected from (a-1), (a-2), (a-3), (a-4), (a-9), (a-10), (a-12), (a-13), (a-14), (a-16) or (a-18).
  • R4 represents hydrogen; f) n is 2.
  • Ri represents especially ethyl or propyl
  • R 2 represents halo, especially chloro or fluoro
  • Z represents a cyclic ring system selected from (a-1), (a-2), (a-9), (a-10) or (a-13);
  • e) t represents hydrogen;
  • f) n is 2.
  • Ri represents ethyl or propyl
  • R 2 represents chloro or fluoro
  • Z represents cyclic ring system (a-9)
  • e) 4 represents hydrogen
  • f) n is 2.
  • Preferred compounds of formula (I) are compounds 31, 6, 27, 9, 24, 40, 25, 7, 26, 45, 48, 49, 43, 36, 16, 28, 33, 32, 34, 51, 52 or 53; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymo ⁇ hic form or a stereochemically isomeric form thereof.
  • More preferred compounds of formula (I) are compounds 26, 48, 43, 52 or 53, especially compound 26, 43 or 53; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymo ⁇ hic form or a stereochemically isomeric form thereof.
  • a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- propyl]-5-isoxazol-5-yl-2-thioxo-2,3-cl ydro-lH-imidazole-4-carboxylic acid methyl ester, a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a polymo ⁇ hic form thereof; a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- ⁇ ropyl]-5-isoxazol-5-yl-2-1hioxo-2,3- ⁇ ydro-lH-imidazole-4-carboxylic acid methyl ester or a N-oxide thereof; a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl
  • compounds of formula (I) wherein R 3 represents hydrogen can be prepared by reacting an intermediate of formula (l-a) or (Il-b) with KSC ⁇ in the presence of a suitable acid, such as for example hydrochloric acid and the like, and a suitable solvent, such as for example an alcohol, e.g. ethanol, optionally in the presence of water.
  • a suitable acid such as for example hydrochloric acid and the like
  • a suitable solvent such as for example an alcohol, e.g. ethanol, optionally in the presence of water.
  • Compounds of formula (I-b) can also be prepared by reacting an intermediate of formula (V) with a suitable base, such as for example sodium hydroxide and the like, in the presence of a suitable solvent, such as for example an alcohol, e.g. ethanol.
  • a suitable base such as for example sodium hydroxide and the like
  • a suitable solvent such as for example an alcohol, e.g. ethanol.
  • Compounds of formula (I) wherein Z represents optionally substituted 1,3,4- oxadiazole, said compounds being represented by formula (I-c), can be prepared by reacting an intermediate of formula (VI) with phosphoric trichloride or Burgess 'reagent optionally in the presence of a suitable solvent, such as for example tetrahydrofuran.
  • Compounds of formula (I) wherein R 3 represents said compounds being represented by formula (I-e), can be prepared by reacting an intermediate of formula (Nil), with an intermediate of formula (VIII), such as for example ⁇ H 3 (or acetic acid ammonium salt), pyrrolidine and the like, in the presence of a suitable solvent, such as for example acetone, tetrahydrofuran, N ⁇ tV-dimethylformamide and the like.
  • a suitable solvent such as for example acetone, tetrahydrofuran, N ⁇ tV-dimethylformamide and the like.
  • Compounds of formula (I) wherein R 3 represents CH 2 -OH, said compounds being represented by formula (I-f), can be prepared by reacting an intermediate of formula (VII) with a suitable reducing agent, such as for example ⁇ aBH in the presence of a suitable solvent, such as for example tefrahydrofuran.
  • a suitable reducing agent such as for example ⁇ aBH
  • a suitable solvent such as for example tefrahydrofuran.
  • compounds of formula (I) wherein the carbon atom carrying the Ri and Rt substituent has the (R) configuration can be prepared according to the above described reactions but starting from an intermediate wherein the carbon atom carrying the Ri and R 4 substituent has the (R) configuration.
  • the compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
  • the compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form.
  • Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g.
  • organic peroxides may comprise peroxy acids such as, for example, benzenecarboper- oxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo- peroxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. teitbutyl hydro-peroxide.
  • Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • Some of the compounds of formula (I) and some of the intermediates in the present in- vention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods.
  • Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compound's into the corresponding enantiomers.
  • suitable resolving agents such as, for example, chiral acids
  • Intermediates of formula (II-a) may be prepared by reacting an intermediate of formula (V JI) wherein W 3 represents a suitable leaving group, such as for example halo, e.g. bromo, with an intermediate of formula (LX) in the presence of a suitable base, such as for example N,N-diisopropylethanamine, and a suitable solvent, such as for example tetrahydrofuran.
  • a suitable base such as for example N,N-diisopropylethanamine
  • a suitable solvent such as for example tetrahydrofuran.
  • a suitable reducing agent such as for example H 2
  • a suitable catalyst such as for example Raney Nickel
  • a suitable catalyst poison such as for example a thiophene solution
  • a suitable base such as for example NH 3 .
  • Intermediates of formula (Il-b) can be prepared by reacting an intermediate of formula (VIII) with an intermediate of formula (XII) in the presence of a suitable solvent, such as for example acetonitrile.
  • Intermediates of formula (XII) can be prepared by reacting an intermediate of formula (XIH) with trimethyloxonium and tetrafluoroborate in the presence of a suitable solvent, such as for example methylenechloride.
  • Intermediates of formula (III) can be prepared from an intermediate of formula (XV) in the presence of formic acid or a formate, such as for example n-butylformate, and in the presence of a suitable solvent, such as for example xylene.
  • formic acid or formate such as for example n-butylformate
  • Stereospecific intermediates of formula (XV-a) can also be prepared by reacting an intermediate of formula (XV) with a suitable stereospecific resolution agent, such as for example [S-(R*,R*)]-2,3-bis[(4-methylbenzoyl)oxy]-butanedioic acid, in the presence of a suitable solvent, such as for example an alcohol, e.g. 2-propanol.
  • a stereospecific intermediate of formula (XV-a) is reacted further according to the methods described hereinabove, the resulting intermediates are also stereospecific and finally the resulting final compounds are also stereospecific.
  • Intermediates of formula (XV) wherein R 4 represents hydrogen, said intermediates being represented by formula (XV-b), can also be prepared by reacting an intermediate of formula (XXVI) with an intermediate of formula (XXVTI) in the presence of a suitable reducing agent, such as for example H 2 , a suitable catalyst, such as for example Pd on charcoal, a suitable catalyst poison, such as for example a thiophene solution, a suitable weak base, such as for example KF or potassium acetate, a suitable acid, such as for example hydrochloric acid, and a suitable solvent, such as for example an reducing agent, such as for example H 2 , a suitable catalyst, such as for example Pd on charcoal, a suitable catalyst poison, such as for example a thiophene solution, a suitable weak base, such as for example KF or potassium acetate, a suitable acid, such as for example hydrochloric acid, and a suitable solvent, such as for example an
  • Intermediates of formula (XVH) can be prepared by reacting an intermediate of formula (XVIII) with diphenylphosphoryl azide in the presence of 2,3,4,6,7,8,9,10- ortahydro-pyrimido[l,2-a]azepine and in the presence of a suitable solvent, such as for example toluene.
  • Stereospecific intermediates of formula (XNIII) wherein R4 is hydrogen and Ri is methyl, ethyl, or n-propyl, said Ri being represented by ⁇ lk and said intermediates being represented by formula (XVffl-a) and (XVTII-b), can be prepared by reacting an intermediate of formula (XLX) with ZnAlk 2 wherein Alk represents methyl, ethyl or n-propyl, in the presence of a stereospecific catalyst, such as for example N,N'-( 1 R,2R)- 1 ,2-'cyclohexanediylbis [1,1,1 -trifluoro] -methanesulfonamide respectively N T-(l S,2S)- 1 ,2-cycIohexanediylbis[l , 1 ,1 -trifluoro]-methanesulfonamide respectively N T-(l S,2S)- 1 ,2-cycIo
  • Intermediates of formula (V) can be prepared by reacting an intermediate of formula (XX) wherein W 5 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, with an intermediate of formula (IX) and an intermediate of formula (XXI), in the presence of a suitable base, such as for example N,N- diisopropylethanamine, and a suitable solvent, such as for example tetrahychofuran.
  • a suitable base such as for example N,N- diisopropylethanamine
  • a suitable solvent such as for example tetrahychofuran.
  • Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (XXII) wherein W ⁇ represents a suitable leaving group, such as for example halo, e.g. chloro, with an intermediate of formula (XXTH) in the presence of a suitable solvent, such as for example tetiahydrofuran, optionally in the presence of a suitable base, such as for example N,N-diethylethanamine.
  • a suitable solvent such as for example tetiahydrofuran
  • a suitable base such as for example N,N-diethylethanamine.
  • Intermediates of formula (XXTV) can be prepared by reacting an intermediate of formula (III) with an intermediate of formula (XXVT) in the presence of KSCN, NaOC(CH 3 ) 3 , a suitable acid, such as for example hydrochloric acid, and a suitable solvent, such as for example tetrahydrofuran. This reaction also leads to the preparation of intermediates of formula (XXV).
  • Intermediates of formula (XXTV) can also be prepared by hydrolyzing an intermediate of formula (XXV) in the presence of a suitable base, such as for example sodium hydroxide, in the presence of a suitable solvent, such as an alcohol, e.g. methanol, and water.
  • a suitable base such as for example sodium hydroxide
  • a suitable solvent such as an alcohol, e.g. methanol, and water.
  • Intermediates of formula (XXTV) may also be prepared by hydrolysis of an intermediate of formula (XXV) in the presence of a suitable acid, such as for example trifluoroacetic acid, in the presence of a suitable solvent, such as for example methylene chloride.
  • the intermediates of formula (LX) may contain a chiral center at the carbon atom carrying the Ri and R4 substituent depending on the substituents representing Ri and R «.
  • a preferred embodiment of the intermediates of formula (IX) are those intermediates wherein the intermediate is stereospecific, i.e. wherein the intermediate has the (R) or (S) configuration at the carbon atom carrying the R] and R t substituent (intermediates of formula (EX-b).
  • Particularly preferred are those intermediates of formula (LX-b) which have the (S) configuration (intermediates of formula (LX-b-1).
  • the present invention also relates to intermediates of formula (IX-b-1)
  • a further embodiment are those intermediates of formula (LX-b-1) wherein n is 1, 2, or 3, in particular 2, provided that when n is 2 and each R 2 is chloro and said two chloro substituents are placed in meta and para position, then Ri is other than ethyl. .appel
  • EX-a-l (EX-b-l-l) a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof, wherein Alk is defined as hereinabove, i.e. Alk represents methyl, ethyl and n-propyl, and each R 2a and R 2b independently represents chloro, fluoro or trifluoromethyl.
  • intermediates of formula (EX-a-l) are those intermediates of formula (IX-a-1) provided that when R 2a and R 2b are both chloro, then Alk is other than methyl, ethyl, n-propyl and provided that when R 2a and R 2 b are both fluoro or R 2a is trifluoromethyl and R 2 b is fluoro or R 2a is fluoro and R 2b is trifluoromethyl then Alk is other than ethyl.
  • a particular interesting intermediate of formula (EX-b-l-l) is that intermediate wherein R 2a and R 2 b are both fluoro and Alk represents ethyl, i.e. a compound of formula (EX-b- 1-1-a). (EX-b-l -l -a)
  • the compounds of formula (I) and (V) show CCR2 receptor antagonistic properties.
  • CCR2 C - C chemokine receptor 2
  • MCP-1 monocyte chemoattractant protein
  • Chemokines are most important regulators of leukocyte trafficking. This biological role is exerted by interacting - on target cells - with seven-transmembrane-domain receptors that are coupled to heterodimeric G proteins. Chemokines are mainly grouped into 2 major families (C - C or C - X - C family) dependent on the presence of an amino acid (represented by X) between the two conserved cysteine residues (represented by C) near the amino terminus. In general, chemokines from the C - C family attract monocytes, macrophages, T cells and NK cells.
  • a chemokine which acts through the CCR2 receptor, is MCP-1 as indicated above. Therefore, the CCR2 receptor is also known as the MCP-1 receptor. MCP-2, MCP-3 and MCP-4 may also act, at least in part, through this receptor.
  • CCR2 receptor antagonists which block the CCR2 receptor, have potential as pharmaceutical agents to combat inflammatory conditions such as arthritis, osteoarthritis, rheumatoid arthritis, glomerulonephritis, diabetic nephropathy, lung fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, vasculitis, hepatitis, nonalcoholic steatohepatitis, inflammatory conditions of the brain such as Alzheimer's disease, restenosis, alveolitis, asthma, allergic rhinitis, allergic conjunctivitis, atherosclerosis, psoriasis, delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease, acute or chronic brain inflammation, e.g.
  • CCR2 receptor antagonists may also be useful to treat autoimmune diseases such as diabetes or transplant rejection, stroke, reperfusion injury, ischemia, cancer, myocardial infraction, pain, in particular neuropathic pain.
  • the compounds of the present invention may also be used to inhibit the entry of Human Immunodeficiency Virus (HTV) into monocytes and lymphocytes, thereby having a therapeutic role in the treatment of AIDS (Acquired Immunodeficiency Syndrome).
  • HTV Human Immunodeficiency Virus
  • the CCR2 receptor exists in two isoforms, namely the CCR2A and the CCR2B receptor.
  • the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines, polymo ⁇ hic forms or stereochemically isomeric forms are useful in the treatment or prevention, in particular for the treatment, of diseases or conditions mediated through the activation of the CCR2 receptor, in particular the CCR2B receptor.
  • Diseases or conditions related to an activation of the CCR2 receptor comprise inflammatory conditions such as arthritis, osteoarthritis, rheumatoid arthritis, glomerulonephritis, diabetic nephropathy, lung fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, vasculitis, hepatitis, nonalcoholic steatohepatitis, inflammatory conditions of the brain such as Alzheimer's disease, restenosis, alveolitis, asthma, allergic rhinitis, allergic conjunctivitis, atherosclerosis, psoriasis, delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease, acute or chronic brain inflammation, e.g.
  • the compounds of formula (I) are useful in the treatment or prevention of inflammatory diseases and autoimmune diseases, especially rheumatoid arthritis, atherosclerosis, multiple sclerosis, inflammatory bowel disease and chronic obstructive pulmonary disease (COPD).
  • the compounds of formula (I) are also of particular interest in the treatment or prevention of psoriasis, asthma, rheumatoid arthritis or pain (neuropathic pain), more in particular psoriasis, asthma or rheumatoid arthritis.
  • the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms may be used as a medicine.
  • the present compounds can be used for the manufacture of a medicament for treating or preventing diseases mediated through activation of the CCR2 receptor, in particular the CCR2B receptor.
  • the compounds of the invention can be used for the manufacture of a medicament for treating or preventing inflammatory diseases, especially rheumatoid arthritis, atherosclerosis, multiple sclerosis, inflammatory bowel disease and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention can also in particular be used for the manufacture of a medicament for treating or preventing psoriasis, asthma, rheumatoid arthritis or pain (neuropathic pain), more in particular psoriasis, asthma or rheumatoid arthritis.
  • a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from diseases mediated through activation of the CCR2 receptor, in particular mediated through the CCR2B receptor comprise the administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine, a polymo ⁇ hic form or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
  • the blockade of the CCR2 receptor by the present compounds of formula (I) inhibits the normal function of MCP-1. Therefore, the present compounds can also be described as MCP-1 inhibitors and hence can be used to prevent or treat diseases mediated through MCP- 1.
  • compositions for preventing or treating diseases mediated through activation of the CCR2 receptor, in particular the CCR2B receptor comprise a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the compounds of the present invention may be formulated into various pharmaceutical forms for administration pu ⁇ oses.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
  • the compounds of the present invention may also be topically administered in the form of drops, in particular eye drops.
  • Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the Uke, and segregated multiples thereof.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the compounds of formula (I) may also be used in combination with other conventional anti-inflammatory or immunosuppressive agents, such as steroids, cyclooxygenase-2 inhibitors, non-steroi ⁇ tel-anti-mflammatory drugs, TNF- ⁇ antibodies, such as for example acetyl salicylic acid, bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen, naproxen, naproxen sodium, tiaprofen acid, flurbiprofen, mefenamic acid, nifluminic acid, meclofenamate, indomethacin, proglumetacine, ketoprofen, nabumetone, paracetamol, piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, beclomethasone dipropionate, betamethasone, beclametha
  • the present invention also relates to the combination of a compound of formula (I) and another anti-inflammatory or immunosuppressive agent. Said combination may be used as a medicine.
  • the present invention also relates to a product containing (a) a compound of formula ( , and (b) another anti-inflammatory or immunosuppressive compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases mediated through activation of the CCR2 receptor, in particular mediated through the CCR2B receptor.
  • the different drugs in such products may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • such products may comprise, for example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing another anti-inflammatory or immunosuppressive compound.
  • a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing another anti-inflammatory or immunosuppressive compound.
  • RT room temperature
  • DIPE tefrahydrofuran
  • DIPE diisopropylether
  • THF trifluoroacetic acid
  • DBU 2,3,4,6,7,8,9, 10-octahydropyrimido[ 1 ,2-a]azepine
  • DMF means N,N-dimethylformamide
  • Example Al a. Preparation of intermediate 1 A solution of ⁇ a 2 C0 3 (part of 0.52 mol) in H 2 0 (150 ml) was added to a stirring mixture of l-(3,4-dichlorophenyl)-l-propanone (0.345 mol) in ethanol, p.a. (150 ml), then the remainder of Na 2 C0 3 was added and hydroxylamine monohydrochloride (0.345 mol) was added portionwise while stirring vigorously. The reaction mixture was heated to reflux temperature and extra H 2 0 (75 ml) was added, then the resulting mixture was stirred and refluxed for 6 hours.
  • Example ⁇ 4 a Preparation of intermediate 9
  • a solution of intermediate 2 (prepared according to Al.b) (0.0748 mol) and chloro acetic acid methyl ester (0.08 mol) in DMF, p.a., dried on molecular sieves, (150 ml) was stirred at room temperature under N and Et 3 N (0.224 mol) was slowly added, then the reaction mixture was stirred for 20 hours at room temperature and extra chloro acetic acid methyl ester (3.3 ml) was added. The mixture was stirred for another 20 hours at room temperature and again extra chloro acetic acid methyl ester (2 ml) was added. The resulting mixture was stirred for 24 hours and then the solids were filtered off and washed with DMF.
  • Intermediate 20 can be prepared by the above reaction by using N,N'-(l S,2S)-1,2- cyclohexanediylbis[ 1,1,1 -trifluoromethanesulfonamide] as catalyst. b-1 .
  • Example A8 a Preparation of intermediate 30 (R) A solution of N,N'-(l S,2S)- 1 ,2-cyclohexanediylbis[l ,1,1 -trifluoromethanesulfonamide] (catalytic quantity) and tetrakis(2-propanolato)titanium (0.415 mol) in toluene (p.a) (500 ml) was degassed under Argon and then stirred for 20 minutes at 1 40 °C. This mixture was cooled on a 2-propanol C ⁇ 2 bath to -78 °C and diethylzinc (0.415 mol) was added dropwise over 15 minutes.
  • Table 1 lists intermediates of formula (IX) which can be prepared according to one of the above
  • the HPLC gradient was supplied by a Waters Alliance HT 2790 system with a columnheater set at 40°C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS Cl 8 column (3.5 ⁇ m, 4.6 x 100 mm) (12 minutes column) with a flow rate of 1.6 ml/minutes.
  • PDA photodiode array
  • mobile phase A 95% 25mM ammoniumacetate + 5% acetonitrile
  • mobile phase B acetonitrile
  • mobile phase C methanol
  • Mass spectra were acquired by scanning from 100 to 1000 in Is using a dwell time of 0.1 s.
  • the capillary needle voltage was 3kV and the source temperature was maintained at 140°C .
  • Nitrogen was used as the nebulizer gas.
  • Cone voltage was 10 V for positive ionzation mode and 20 V for negative ionization mode.
  • Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • the HPLC gradient was supplied by a Waters Alliance 2690 system with a columnheater set at 50°C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode.
  • PDA photodiode array
  • Reversed phase HPLC was carried out on a Xterra MS Cl 8 column (2.5 ⁇ m, 4.6 x 20 mm) with a flow rate of 3 ml/min.
  • Three mobile phases (mobile phase A 95% 25mM ammoniumacetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50% B and 50% C in 0.9 min., to 100 % B in 0.37 min, 100% B for 0.18 min. and reequilibrate with 100 % A for 0.2 min.
  • An injection volume of 2 ⁇ L was used.
  • Mass spectra were acquired by scanning from 100 to 1000 in Is using a dweU time of 0.1 s.
  • the capillary needle voltage was 3kV and the source temperature was maintained at 140°C .
  • Nitrogen was used a the nebulizer gas.
  • Cone voltage was 10 V for positive ionzation mode and 20 V for negative ionization mode.
  • Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • MCP-1 binding to the CCR2 receptor induces a rapid and transient intracellular release of Ca 2+ (secondary messenger) in several cell lines (Charo et al, PNAS 1994). Free Ca 2+ levels can be measured using a Ca 2+ sensitive dye. When the CCR2 receptor is blocked with a CCR2 receptor antagonist, the MCP-1 induced release of Ca 2+ is inhibited.
  • Human THP-1 cells (monocytic cell line, ATCC TIB-202) were cultured in RPMI 1640 medium supplemented with 10 % fetal calf serum (FCS), 1% L-Glulamine, penicillin (50 U/ml) and streptomycin (50 ⁇ g/ml) (all GIBCO BRL, Gent). After centrifugation, cells were loaded for 30 minutes with the Ca 2+ sensitive fluorescent dye Fluo-3 AM (Molecular Probes, Leiden, Netherlands) (2 milUon cells/ml in RPMI medium containing 4 ⁇ M Fluo-3 AM, 20 mM HEPES, 0.1 % Bovine Serum Albumin (BSA) and 5 mM probenecid).
  • FCS fetal calf serum
  • BSA Bovine Serum Albumin
  • Table 5 reports ⁇ IC 5 o values obtained in the above-described test for compounds of formula (I).
  • pICso defines -log IC50 wherein IC50 is the molar concentration of the test compound which inhibits 50 % of specific MCP-1 induced Ca 2+ flux.
  • Binding buffer was composed of 25 mM HEPES, 5 mM MgCl 2 , 1 mM CaCl 2 , 0.5% protease-free bovine serum albumin, pH 7.4. After 90 minutes incubation at 25 °C, membranes were harvested on GF/B filters - presoaked in 0.5% polyethylenimine, foUowed by washing with buffer containing 25 mM HEPES, 5 mM MgCl 2 , 1 mM CaCl 2 , 5 mM NaCl, pH 7.4. Filter bound radioactivity was determined by liquid scintillation counting. EC 50 values ( ⁇ M) and K values ( ⁇ M) were calculated.
  • the EC 50 value indicates the concentration of the test compound that competes with MCP-1 for half of the specific binding sites; the value indicates the equilibrium dissociation constant, i.e. the concentration of the test compound that will bind to half of the binding sites at equilibrium in the absence of radioligand or other competitors.
  • EC 50 values and Kj values were calculated using non-linear regression in Graphpad Prism. Prism calculates the Kj or affinity of the receptor for the competing drug using the equation of Cheng and Prusoff (Biochem. Pharmacol. 1973, 22: 3099- 3108). A low Kj indicates a high affinity of the receptor for the test compound. EC.
  • K ; 50 [radioligand] 1 + K A wherein I describes the affinity of the radioligand for the receptor, i.e. the concentration of the radioligand that will bind to half of the binding sites at equilibrium in the absence of competitors.
  • Table 6 lists K values ( ⁇ M) obtained in the above-described test for compounds of formula (I).
  • the CCR2 antagonistic activity of the compounds of the present invention can also be determined by measuring the effect of the compounds on the chemotactic response of cells in the presence of a chemokine, such as for example MCP-1.
  • a chemokine such as for example MCP-1.
  • Mononuclear cells from human heparinized peripheral blood (PBMC) were isolated using Ficoll-Paque gradient centrifugation (Amersham Biosciences). Assays of chemotactic responsiveness were performed using disposable 96-well chemotaxis chambers (ChemoTx, Neuro Probe) with 5- ⁇ m pore size polycarbonate (PVP-free) filter membranes. Mononuclear cells were fluorescently labeled with 5 ⁇ g/ml Calcein- AM (Molecular Probes, Eugene, OR) at 37°C for 30 minutes.
  • CL chemotactic index
  • Table 7 lists the IC 50 values ( ⁇ M) obtained in the above-described test for compounds of formula (I). Assays were run in triplicate and repeated 2-7 times.

Abstract

The present invention relates to a compound of formula (I) a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymorphic form or a stereochemically isomeric form thereof, wherein R1 represents hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6alkyloxyC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, aryl or heteroaryl; each R2 independently represents halo, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, cyano, aminocarbonyl, amino, mono-or di(C1-4alkyl)amino, nitro, aryl or aryloxy; R3 represents hydrogen, cyano, optionally subst ituted C1-6alkyl, C(=O)-O-R5, C(=O)-NR6aR6b, C(=S)-NR6aR6b, S(=O)2-NR6aR6b or C(=O)-R7; R4 represents hydrogen or C1-6alkyl; n is 1, 2, 3, 4 or 5; Z represents a cyclic ring system. The invention also relates to processes for preparing the compounds of formula (I), their use as CCR2 antagonists and pharmaceutical compositions comprising them.

Description

MERCAPTOIMIDAZOLES AS CCR2 RECEPTOR ANTAGONISTS
The present invention concerns mercaptoimidazole derivatives having CCR2 receptor antagonistic properties. The invention further relates to methods for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of diseases mediated through activation of the CCR2 receptor, in particular the CCR2B receptor. WO 02/066458 describes 2-thio-substituted imidazole derivatives having immunomodulating and/or inhibiting activity on the release of cytokines, especially TNF-α and IL-β. FR 1,487,326 relates to tMo-imidazole derivatives useful as analgetic and for its vasodilatation activity. FR 6,751 M describes io-imidazole derivatives as sedatives and analgesics. US 3,850,944 describes 2-mercapto-5-(3-ρyridyl)-imidazole derivatives having antiinflammatory activity. Bull. Soc. Chim.Belg., 73, ppl81-188 (1964) describes the synthesis and properties of α-arylali lamines. Archiv der Pharmazie, 305 (12), pp891-901 (1972) describes the synthesis and pharmacology of N-chloracyl-benzylamines. Annales pharmaceutiques francaises, 29(1), pp 63-70 (1971) describes the synthesis of imidazole derivatives. The compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity and/or pharmacological potency.
Figure imgf000002_0001
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymorphic form or a stereochemically isomeric form thereof, wherein Ri represents hydrogen,
Figure imgf000002_0002
C3-7cycloalkyl,
Figure imgf000002_0003
di(C]-6alkyl)aminoCι-6alkyl, aryl or heteroaryl; each R2 independently represents halo, C]-6alkyl, Cι_δalkyloxy, Ci ^alkylthio, polyhaloCi-βalkyl,
Figure imgf000003_0001
cyano, aminocarbonyl, amino, mono-or
Figure imgf000003_0002
nitro, aryl or aryloxy; R3 represents hydrogen, cyano, Ci-βalkyl optionally substituted with hydroxy or 2 Ci-ealkyloxy, C(=0)- or C(=0)-R7; 4 represents hydrogen or
Figure imgf000003_0003
R5 represents hydrogen, Ci-βalkyl, hydroxyCi-ealkyl, C2-$alkenyl, C2-6alkynyl,
Figure imgf000003_0004
aminoCι.6alkyl, mono-or
Figure imgf000003_0005
aminocarbonylCi-6alkyl, mono-or di^i^alky^aminocarbonylCi-βalkyl or aryl; Rβa and Rδb each independently represent hydrogen, C^aHcyl, amino, mono-or di(Cι-4alkyl)amino, arylNH-, aminoCi-βalkyl, mono-or di(Cι-4alkyl)amino- Cι-6alkyl,
Figure imgf000003_0006
aminocarbonylamino, Ci-βalkyloxy, carbonylamino or hydroxyCι-6alkyl; or
Rβa and Rβb taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, moφholinyl, thiomorpholinyl or piperazinyl substituted with C^alkyl; R represents hydrogen,
Figure imgf000003_0007
hydroxyCi-βalkyL C2-6alkenyl, C2-6alkynyl, polyhaloCi-βalkyl,
Figure imgf000003_0008
aminoCi-βalkyl, mono-or di(C1- alι^l)aminoCι^alkyl, aminocarbonylCi-βalkyl, mono-or d^Ci-Aalky^aminocarbonylCi-ealkyl, aryl or heteroaryl; Z represents a cyclic ring system selected from
Figure imgf000004_0001
(a-1) (a-2) (a-3) (a-4) (a-5) (a-6)
Figure imgf000004_0002
(a-7) (a-8) (a-9) (a-10) (a-11) (a-12)
Figure imgf000004_0003
(a-14) (a-15) (a-17) (a-16)
Figure imgf000004_0004
(a-18) each Rg independently represents hydrogen, halo,
Figure imgf000004_0005
polyhaloCi-βalkyl, polyhaloCi-βalkyloxy, cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyI, amino, mono-or di(Cι-4alkyl)amino, hydroxyCi-δalkylamino, aryl, aryloxy, piperidinyl, piperidmylamino, morpholinyl, piperazinyl or nitro; each R9 independently represents hydrogen, halo or Ci-βalkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo,
Figure imgf000004_0006
polyhaloCi-galkyl, polyhaloCi-ealkyloxy, cyano, aminocarbonyl, mono-or di(Ci-4alkyl)aminocarbonyl, amino, mono-or ώ(Cι-4alkyl)aιnino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo, Cι-6alkyl, Ci-βalkyloxy,
Figure imgf000005_0001
cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino or nitro; provided that l-(3,4-(umemoxybenzyl)^^henyl-lH-imidazole-2-thiol; and l-(o-chlorobenzyl)-5-ethyl-4-phenyl-imidazole-2-thiol are not included.
The present invention also relates to the use of a compound for the manufacture of a medicament for preventing or treating diseases mediated through activation of the
CCR2 receptor, in particular for preventing or treating inflammatory diseases, wherein said compound is a compound of formula (I)
Figure imgf000005_0002
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof, wherein Ri represents hydrogen, Chalky!, C3-7cycloalkyl,
Figure imgf000005_0003
di(Cι-6alkyl)aminoC1^alkyl, aryl or heteroaryl; each R2 independently represents halo, Ci-βalkyl, Ci-βalkyloxy,
Figure imgf000005_0004
polyhaloCi-βalkyl, polyhaloCi-δalkyloxy, cyano, aminocarbonyl, amino, mono-or di(Cι-4aιkyl)amino, nitro, aryl or aryloxy;
R3 represents hydrogen, cyano, -δalkyI optionally substituted with hydroxy or Ci-βalkyloxy, C(=0)-0-R5, C(=0)-N 6a 6b, C(=S)-NR6aR6b, S^O^-N ^R^ or C(=0)-R7; R» represents hydrogen or Ci-βalkyl; 5 represents hydrogen, Ci-βalkyl, hydroxyCi-ealkyl, C2^alkenyl, C^alkynyl,
Figure imgf000005_0005
aminoCι.6alkyl, mono-or di(Cι^alkyl)aminoCι-6alkyl, aminocarbonylCi-βalkyl, mono-or di(Ci-4alkyl)aminocarbonylCi-6alkyl or aryl; Rga and R«, each independently represent hydrogen, Ci-βalkyl, amino, mono-or difC alky amino, arylNΗ-, aminoCi-ealkyl, mono-or di(Cι-4alkyl)amino Ci-βalkyl,
Figure imgf000005_0006
aminocarbonylamino, G-βalkyloxy, carbonylamino or hydroxyCι-6alkyl; or δa and R^, taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, moφholinyl, thiomoφholinyl or piperazinyl substituted with Ci-βalkyl;
R7 represents hydrogen, Ci-ealkyl, hydroxyCi-βalkyl, C2-6alkenyl, C2-6alkynyl, polyhaloCi-βalkyl, Ci-salkyloxyG-ealkyl, aminoCi-ealkyl, mono-or
Figure imgf000006_0001
aminocarbonylCi-δalkyl, mono-or d^Ct-italky^aminocarbonylCi-δalkyl, aryl or heteroaryl;
Z represents a cyclic ring system selected from
Figure imgf000006_0002
(a-1) (a-2) (a-3) (a-4) (a-5) (a-6)
Figure imgf000006_0003
(a-7) (a-8) (a-9) (a-10) (a-11) (a-12)
Figure imgf000006_0004
(a-18) each Rg independently represents hydrogen, halo,
Figure imgf000006_0005
G-βalkyloxy, polyhaloCi-ealkyl, polyhaloCι-6alkyloxy, cyano, aminocarbonyl, mono-or
Figure imgf000006_0006
amino, mono-or di(Cι-4alkyl)amino, hydroxyCι-6alkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, moφholinyl, piperazinyl or nitro; each R9 independently represents hydrogen, halo or Ci-βalkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Chalky!,
Figure imgf000007_0001
polyhaloCi-βalkyl, polyhaloG-δalkyloxy, cyano, aminocarbonyl, mono-or di(Cι-4a]kyl)aminocarbonyl, amino, mono-or di(Cι_4alkyl)amino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo, Chalky!,
Figure imgf000007_0002
cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino or nitro.
More in particular, the present invention also relates to the use of a compound for the manufacture of a medicament for preventing or treating diseases mediated through activation of the CCR2 receptor, in particular for preventing or treating inflammatory diseases, wherein said compound is a compound of formula (I)
Figure imgf000007_0003
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof, wherein Ri represents hydrogen, Ci-βalkyl, C3-7cycloalkyl,
Figure imgf000007_0004
di G-δalkylJaminoCi-δalkyl, aryl or heteroaryl; each R2 independently represents halo, G-βalkyl, Cι_6alkyloxy, Ci-βalkylthio,
Figure imgf000007_0005
polyhaloCi-ealkyloxy, cyano, aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino, nitro, aryl or aryloxy;
R3 represents hydrogen, cyano, Ci-όalkyl optionally substituted with hydroxy or C1-6alkyloxy,
Figure imgf000007_0006
or C(=0)-R7; R-i represents hydrogen or G-βalkyl; R5 represents hydrogen, C^alkyl, hydroxyC^alkyl, C2-6alkenyl, C2-6alkynyL, polyhaloCι-6alkyI, Ci-ealkyloxyCi-βalkyl, aminod-βalkyl, mono-or
Figure imgf000007_0007
d^Ci^alky^aminocarbonylCi-ealkyl or aryl; Rβa and Rβb each independently represent hydrogen, Ci-βalkyl, amino, mono-or di(G-4alkyl)amino, arylNH-, aminoCi-δalkyl, mono-or di(Cι-4alkyl)amino Cι-6alkylcarbonylamino, aminocarbonylamino, Cι-6alkyloxy, carbonylamino orhydroxyCi-ealkyl; or
Rβa and R^b taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, moφholinyl, thiomoφholinyl or piperazinyl substituted with G-βalkyl;
R7 represents hydrogen, G-ealkyl,
Figure imgf000008_0001
C2-6alkenyl, C2-6alkynyl,
Figure imgf000008_0002
aminoCi-βalkyl, mono-or di(Cι-4aιkyl)aminoCι-6alkyl, aminocarbonylCi-βalkyl, mono-or d^C alky^aminocarbonylCi-βalkyl, aryl or heteroaryl;
Z represents a cyclic ring system selected from
Figure imgf000008_0003
(a-1) (a-2) (a-3) (a-4) (a-5) (a-6)
Figure imgf000008_0004
(a-7) (a-8) (a-9) (a-10) (a-11) (a-12)
Figure imgf000008_0005
(a-18) each Rg independently represents hydrogen, halo, Chalky 1, G-βalkyloxy, polyhalod-βalkyl, polyhaloCi-βalkyloxy, cyano, aminocarbonyl, mono-or di(Ci-4alkyl)aminocarbonyl, amino, mono-or
Figure imgf000008_0006
hydroxyCi-βalkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, moφholinyl, piperazinyl or nitro; each R9 independently represents hydrogen, halo or G-βalkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Chalky., Cj-βalkyloxy, polyhaloC^alkyl, polyhaloG-βalkyloxy, cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyl, amino, mono-or di(Cι-4alleyl)arnino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo,
Figure imgf000009_0001
polyhaloCi-βalkyl,
Figure imgf000009_0002
cyano, aminocarbonyl, mono-or di(Cι-4alkyι)aminocarbonyl, amino, mono-or di(Ci-4alkyl)amino or nitro; provided that
1 -(3,4-dimethoxybenzyl)-4-phenyl- lH-iιtύdazole-2-thiol; and l-(o-chloroberιzyl)-5-ethyl-4-phenyl-imidazole-2-thiol are not included.
A particular embodiment of the present invention are those compounds of formula (I) as defined hereinabove or hereinafter provided that l-(3,4-dimethoxybenzyl)-4-phenyl- lH-imidazole-2-thiol; l-(o-chlorobenzyl)-5-e yl-4-phenyl-imidazole-2-thiol or pharmaceutically acceptable addition salts thereof are not included.
As used hereinbefore or hereinafter
Figure imgf000009_0003
as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl; G^alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for Cι-4alkyl and pentyl, hexyl, 2-methylbutyl and the like; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; C2-<salkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C^alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
As used hereinbefore, the term (=0) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing or hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloCι-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted Chalky!, for example, the groups defined in polyhalomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhalomethyl or
Figure imgf000010_0001
they may be the same or different.
The term heteroaryl in the definition of Ri or R7 is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl comprises lH-pyrrolyl and 2H-pyrrolyl.
The aryl, heteroaryl, heterocyclic ring systems or cyclic ring systems listed in the definitions of the substituents of the compounds of formula (I) (see for instance Rj, R5, R and Z) as mentioned hereinabove or hereinafter may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when heteroaryl is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.
When any variable (eg. R^, Rβ ) occurs more than one time in any constituent, each definition is independent.
Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms. When the lines are drawn into bicyclic ring systems, it indicates that the bond may be attached to any of the suitable ring atoms of any one of the two cycles of the bicyclic ring system.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxy- acetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-l,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfo ic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propyla ine, isopropylamine, the four bulylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n- butylamine, pyrrolidine, piperidine, moφholine, trimethylamine, triethylamine, tripropylamine, quinucUdine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l, 3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl7-toluenesulfonates. A quaternary amine has a positively charged nitrogen.
Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
It will be appreciated that some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines, polymoφhic forms or stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term "stereochemically isomeric forms" as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines, polymoφhic forms or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates, quaternary amines or polymoφhic forms substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Thus, when a compound of formula (I) is for instance specified as (E), this means that the compound is substantially free of the (Z) isomer. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans- configuration. Compounds encompassing double bonds can have an E (entgegen) or Z (zusammen) -stereochemistry at said double bond. The terms cis, trans, R, S, E and Z are well known to a person skilled in the art. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention. Polymoφhic forms of the present compounds also fall within the ambit of the present invention. The term "polymoφhic forms" as used hereinbefore or hereinafter defines all possible crystalline arrangement of a particular compound. A polymoφhic form of a compound is the same chemical entity, but in a different crystalline arrangement. The term "polymoφhic form" is well-known to a person skilled in the art.
Polymoφhic forms of pharmaceutical compounds may be of interest to those involved in the development of a suitable dosage form because if the polymoφhic form is not held constant during clinical and stability studies, the exact dosage used or measured may not be comparable from one lot to the next. Once a pharmaceutical compound is produced for use, it is important to recognize the polymoφhic form delivered in each dosage form to assure that the production process use the same form and that the same amount of drug is included in each dosage. Therefore, it is imperative to assure that either a single polymoφhic form or some known combination of polymoφhic forms is present. In addition, certain polymoφhic forms may exhibit enhanced thermodynamic stability and may be more suitable than other polymoφhic forms for inclusion in pharmaceutical formulations.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula (I) are intended to be included within the scope of the present invention. For instance, it is intended that
formula (I) includes the tautomeric form of NH being N . Thus, the compounds of the present invention include compounds of formula
Figure imgf000013_0001
Whenever used hereinafter, the term "compounds of formula (I)" is meant to also include their N-oxide forms, their addition salts, their quaternary amines, their polymoφhic forms or their stereochemically isomeric forms. Of special interest are those compounds of formula (I) which are stereochemically pure. Whenever used hereinbefore or hereinafter that substituents can be selected each independently out of a list of numerous definitions, such as for example for Rea or Rήb, all possible combinations are intended which are chemically possible.
A first interesting embodiment of the present invention relates to a compound of formula
Figure imgf000014_0001
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein Ri represents hydrogen,
Figure imgf000014_0002
C3-7cycloalkyl, Cι_6alkyloxyCι-6alkyl, di(Cι-6alkyl)aminoCι_6alkyl, aryl or heteroaryl; each R2 independently represents halo, Ci-βalkyl,
Figure imgf000014_0003
Ci-βalkylthio, polyhaloCi-βalkyl, polyhaloCi-ealkyloxy, cyano, aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino, nitro, aryl or aryloxy; R3 represents hydrogen, cyano, G-βalkyl optionally substituted with hydroxy or
Figure imgf000014_0004
C(=0)-R7; R-j represents hydrogen or G-βalkyl;
R5 represents hydrogen, G-βalkyl, hydroxyCi-ealkyl, C2-6alkenyL, C2-6alkynyl, polyhaloCi-βalkyl, Ci-βalkyloxyCi-ealkyl, aminoCi-ealkyl, mono-or
Figure imgf000014_0005
aminocarbonylCi-βalkyl, mono-or difCi^alky^aminocarbonylCi-ealkyl or aryl; βa and R«b each independently represent hydrogen,
Figure imgf000014_0006
amino, mono-or di(Cι-4alkyl)amino, arylNH-, aminoCι-6alkyl, mono-or
Figure imgf000014_0007
Figure imgf000014_0008
carbonylamino or hydroxyCι-6alkyl; or Rβa and Rβ taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, moφholinyl, thiomoφholinyl or piperazinyl substituted with Ci-βalkyl; R7 represents hydrogen, Cι_δalkyl, hydroxyG-galkyl, C2-6alkenyl, C2-6alkynyl, polyhaloCi-βalkyl,
Figure imgf000014_0009
aminoG-βalkyl, mono-or di(Cι-4alkyl)aminoCι-6alkyl, aminocarbonylCi-βalkyl, mono-or di(Cι-4alkyl)aminocarbonylCι-6alkyl, aryl or heteroaryl; Z represents a cyclic ring system selected from
Figure imgf000015_0001
(a-1) (a-2) (a-3) (a^) (a-5) (a-^)
Figure imgf000015_0002
(a-7) (a-8) (a-9) (a-10) (a"n) (a"'2)
Figure imgf000015_0003
Figure imgf000015_0004
(a-18) each R« independently represents hydrogen, halo,
Figure imgf000015_0005
G-βalkyloxy, poIyhaloCi-βalkyl, polyhaloG-βalkyloxy, cyano, aminocarbonyl, mono-or di(Ci-4alkyl)aminocarbonyl, amino, mono-or
Figure imgf000015_0006
hyoroxyCι^alkylamino, aryl, aryloxy, piperidinyl, piperidmylamino, moφholinyl, piperazinyl or nitro; each R9 independently represents hydrogen, halo or Chalky]; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, G^alkyl, G-salkyloxy, polyhaloG-βalkyl, polyhaloG-βalkyloxy, cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyl, amino, mono-or di(Cι_4alkyl)amino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo, G-galky],
Figure imgf000016_0001
polyhaloCi-βalky], polyhaloCi-βalkyloxy, cyano, aminocarbonyl, mono-or
Figure imgf000016_0002
amino, mono-or di(Cι- alkyl)amino or nitro; provided that
1 -(3,4-dimethoxybenzyl)-4-phenyl-lH-irnidazole-2-thiol; and l-(o-chlorobenzyl)-5-ethyl-4-phenyl-imidazole-2-thiol are not included.
A second interesting embodiment of the present invention relates to a compound of formula
Figure imgf000016_0003
wherein
Ri represents hydrogen, Cι_6alkyl, C3-7cycloalkyl,
Figure imgf000016_0004
di(Cι -6alkyl)aminoCι ^alkyl, aryl or heteroaryl; each R2 independently represents halo, G-βalkyl,
Figure imgf000016_0005
Ci-βalkylthio, polyhaloCi_6alkyl, polyhaloCi-βalkyloxy, cyano, aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino, nitro, aryl or aryloxy; R3 represents hydrogen, cyano, Cι-6alkyl optionally substituted with hydroxy or Cealkyloxy, C(=0)-0-R5,
Figure imgf000016_0006
or C(=0)-R7; R» represents hydrogen or G-salkyl;
R5 represents hydrogen,
Figure imgf000016_0007
C2_6alkynyl, polyhaloCϊ-βalkyl, Cι-6alkyloxyC1-6alkyl, aminoCi-βalkyl, mono-or
Figure imgf000016_0008
aminocarbonylCi-ealkyl, mono-or di(Cι-4alkyl)aminocarbonylCι-6alkyl or aryl; Rδa and Rβb each independently represent hydrogen, Ci-βalkyl, amino, mono-or di(Cι-4alkyl)amino, arylNH-, aminoCι-6alkyl, mono-or cu(Cι.4alkyl)arrιino- G-βalkyl, Ci-βalkylcarbonylamino, aminocarbonylamino, G^alkyloxy, carbonylamino or hydroxyQ-βalkyl; or
R«a and R«, taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, moφholinyl, thiomoφholinyl or piperazinyl substituted with Chalky!; R7 represents hydrogen, G^alkyl, hydroxyCi ^alkyl, C2_$alkenyl, C2_6alkynyl, polyhaloCi-βalkyl, Ci-ealkyloxyCi-όalkyl, aminoG-ealkyl, mono-or di(Cι-4alkyl)aminoCι-6alkyl,
Figure imgf000017_0001
mono-or d^C alky^aminocarbonylCi-δalkyl, aryl or heteroaryl;
Z
Figure imgf000017_0002
(a-1) (a-2) (a-3) (**) (a-5) (a-6)
Figure imgf000017_0003
(a-7) (a-8) (a-9) (a-10) (a-11) (a-12)
Figure imgf000017_0004
(a-18) each Rg independently represents hydrogen, halo, Chalky!, Ci-βalkyloxy, polyhaloG-ealkyl, polyhaloCi-βalkyloxy, cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino, hydroxyCi-δalkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, moφholinyl, piperazinyl or nitro; each R9 independently represents hydrogen, halo or G^alkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Chalky!,
Figure imgf000017_0005
polyhaloCi-ealkyl, polyhaloQ-βalkyloxy, cyano, aminocarbonyl, mono-or di(Cι^alkyl)aminocarbonyl, amino, mono-or di(Cι^alkyl)amino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo, Ci-βalkyl, G-βalkyloxy,
Figure imgf000018_0001
polyhaloG-βalkyloxy, cyano, aminocarbonyl, mono-or
Figure imgf000018_0002
amino, mono-or difCi-.jalky amino or nitro; provided that
1 -(3,4-dime oxybenzyl)-4-phenyl-lH-imidazole-2-thiol; and l-(o-chlorobenzyl)-5-ethyl-4-phenyl-imidazole-2-thiol are not included.
A third interesting embodiment are the compounds of formula (0 or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R3 represents hydrogen, cyano,
Figure imgf000018_0003
or C(=0)-R7.
A fourth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embcKliment wherein R3 represents cyano, Ci-βalkyl optionally substituted with hydroxy or Cι-6alkyloxy, C(=0)-0-R5,
Figure imgf000018_0004
A fifth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R3 represents cyano, C(=0)-0-R5,
Figure imgf000018_0005
A sixth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R3 represents hydrogen, cyano, C(=0)-0-R5,
Figure imgf000018_0006
or C(=0)-R7; preferably C(=0)-0-R5; more preferably C(=0)-0-Cι-6alkyl; most preferred C(=0)-0-CH3.
A seventh interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Z is other than 3- pyridyl. Λn eight interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Z is a cyclic ring system selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-9), (a-10), (a-11), (a- 12), (a-13), (a- 14), (a- 15) or (a- 16) as defined hereinabove; preferably a cyclic ring system selected from (a-1), (a-2), (a-3), (a-4), (a-9), (a-10), (a- 12), (a- 13), (a- 14), (a- 16) or (a- 18); more preferably a cyclic ring system selected from (a-1), (a-2), (a-3), (a-9), (a-10), (a-12), (a-13), (a-14) or (a-16); even more preferably a cyclic ring system selected from (a-1), (a-2), (a-9), (a-10) or (a-13); most preferred a cyclic ring system of formula (a-9).
A ninth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Z is a cyclic ring system selected from (a-2), (a-7) or (a-9) or a cyclic ring system selected from (a-2), (a-8) or (a-10); preferably wherein Z is a cyclic ring system selected from (a-2), (a-7) or (a-9); more preferably wherein Z is a cyclic ring system selected from (a-2), (a-7) or (a-9) and wherein R3 represents C(=0)-O-Rs.
A tenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein n is 2 or 3; preferably wherein n is 2.
An eleventh interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein n is 2 and said two R2 substituents are placed in meta and para postion.
A twelfth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R2 represents halo, Chalky], G^alkyloxy or polyhaloG-βalkyl; preferably halo or polyhaloQ gally, in particular chloro, fluoro or trifluoromethyl; most preferred halo, in particular chloro or fluoro, more in particular fluoro.
A thirteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Ri is hydrogen, methyl, ethyl, n-propyl, methoxymethyl, cyclohexyl, cyclopropyl, dimethylaminomethyl, 2-thienyl, 3,4-dichlorophenyl; preferably Ri is
Figure imgf000019_0001
or
Figure imgf000019_0002
in particular methyl, ethyl, propyl, methoxymethyl, more in particular methyl, ethyl, n-propyl or methoxymethyl; more preferably Ri is G-6alkyl, in particular methyl, ethyl and propyl, more in particular methyl, ethyl or n-propyl; most preferred Ri is ethyl.
A fourteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein t is hydrogen.
A fifteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment which are stereochemically pure.
A sixteenth interesting embodiment are the compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the carbon atom carrying the Ri and t substituent has the (S) configuration, i.e. a compound of formula
Figure imgf000020_0001
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof.
Also interesting compounds are those compounds of formula (I) wherein one or more, preferably all of the following restrictions apply: a) Ri represents Cι_6alkyl or Ci- alkyloxyCi-ealkyl, especially methyl, ethyl, propyl or methoxymethyl; b) R2 represents halo, polyhaloCi-βalkyl or aryloxy, especially halo, e.g. chloro or fluoro; c) R3 represents hydrogen, cyano, C(=O)-0-R5,
Figure imgf000020_0002
d) Z represents a ring system selected from (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-9), (a-10), (a-11), (a- 12), (a-13), (a-14), (a-15) or (a-16); e) R represents hydrogen; f) n is 2 or 3.
Also interesting compounds are those compounds of formula (I) wherein one or more of the following restrictions apply: a) Ri represents
Figure imgf000021_0001
especially methyl, ethyl, propyl or methoxymethyl; b) R2 represents halo, especially chloro or fluoro; c) R3 represents hydrogen; cyano; C(=0)-0-R5 wherein R5 is preferably hydrogen, Cι-6alkyl or Ci-βalkyloxyCi-ealkyl;
Figure imgf000021_0002
are preferably hydrogen or
Figure imgf000021_0003
C(=0)-R7 wherein R7 is preferably optionally substituted thiazolyl; d) Z represents a ring system selected from (a-1), (a-2), (a-3), (a-4), (a-9), (a-10), (a-12), (a-13), (a-14), (a-16) or (a-18). e) R4 represents hydrogen; f) n is 2.
Further interesting compounds are those compounds of formula (I) wherein one or more of the following restrictions apply: a) Ri represents
Figure imgf000021_0004
especially ethyl or propyl; b) R2 represents halo, especially chloro or fluoro; c) R3 represents C(=0)-0-R5 or
Figure imgf000021_0005
d) Z represents a cyclic ring system selected from (a-1), (a-2), (a-9), (a-10) or (a-13); e) t represents hydrogen; f) n is 2.
Yet further interesting compounds are those compounds of formula (I) wherein one or more of the following restrictions apply: a) Ri represents ethyl or propyl; b) R2 represents chloro or fluoro; c) R3 represents C(=O)-0-R5, especially C(=0)-0-CH3; d) Z represents cyclic ring system (a-9); e) 4 represents hydrogen; f) n is 2.
Preferred compounds of formula (I) are compounds 31, 6, 27, 9, 24, 40, 25, 7, 26, 45, 48, 49, 43, 36, 16, 28, 33, 32, 34, 51, 52 or 53; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof.
More preferred compounds of formula (I) are compounds 26, 48, 43, 52 or 53, especially compound 26, 43 or 53; a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof.
Most preferred is any one of the following : a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- propyl]-5-isoxazol-5-yl-2-thioxo-2,3-cl ydro-lH-imidazole-4-carboxylic acid methyl ester, a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a polymoφhic form thereof; a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- ρropyl]-5-isoxazol-5-yl-2-1hioxo-2,3-α^ydro-lH-imidazole-4-carboxylic acid methyl ester or a N-oxide thereof; a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- propyl]-5-isoxazol-5-yl-2-1hioxo-2,3-d^ydro-lH-irnidazo]e-4-carboxylic acid methyl ester or a pharmaceutically acceptable addition salt thereof; a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro- lH-imidazole-4-carboxylic acid methyl ester or a quaternary amine thereof; a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- propyl]-5-isoxazol-5-yl-2- ioxo-2,3-dihydro-lH-imidazole-4-carboxylic acid methyl ester ; or a compound of formula (I) wherein the compound is (S)-3-[l-(3,4-difluoro-phenyl)- propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-lH-imidazole-4-carboxylic acid methyl ester with a melting point of 128.5°C.
In general, compounds of formula (I) wherein R3 represents hydrogen, said compounds being represented by formula (I-a), can be prepared by reacting an intermediate of formula (l-a) or (Il-b) with KSCΝ in the presence of a suitable acid, such as for example hydrochloric acid and the like, and a suitable solvent, such as for example an alcohol, e.g. ethanol, optionally in the presence of water.
Figure imgf000023_0001
(π-b) Compounds of formula (I) wherein R3 is other than hydrogen, said R3 being represented by R3- and said compounds being represented by formula (I-b), can be prepared by reacting an intermediate of formula (lU) with an intermediate of formula (IV) wherein Wi represents a suitable leaving group, such as for example Ci-βalkyloxy, e.g. methoxy or t-butyloxy, or halo, e.g. chloro and the Uke, in the presence of KSCN, a suitable acid, such as for example hydrochloric acid and the like, a suitable solvent, such as for example tetrahydrofuran, or a mixture of tetrahydrofuran and a suitable alcohol, e.g. methanol, and a suitable base, such as for example t-BuONa, LϊN(isoρropyl)2 orNH[Si(CH3)3].
Figure imgf000023_0002
(ffj) (I-b)
Compounds of formula (I-b) can also be prepared by reacting an intermediate of formula (V) with a suitable base, such as for example sodium hydroxide and the like, in the presence of a suitable solvent, such as for example an alcohol, e.g. ethanol.
Figure imgf000024_0001
(V) (I-b)
Compounds of formula (I) wherein Z represents optionally substituted 1,3,4- oxadiazole, said compounds being represented by formula (I-c), can be prepared by reacting an intermediate of formula (VI) with phosphoric trichloride or Burgess 'reagent optionally in the presence of a suitable solvent, such as for example tetrahydrofuran.
Figure imgf000024_0002
(VI) (I-c)
Compounds of formula (I) wherein R3 represents C(=0)-0-R5- wherein R5> represents or hydroxyCi-βalkyl, said compounds being represented by formula (I-d), can be prepared by reacting an intermediate of formula (VII), wherein W2 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, with an appropriate alcohol of formula HO-R5> in the presence of a suitable solvent, such as for example tetrahydrofuran.
Figure imgf000024_0003
(VH) (I-d)
Compounds of formula (I) wherein R3 represents
Figure imgf000024_0004
said compounds being represented by formula (I-e), can be prepared by reacting an intermediate of formula (Nil), with an intermediate of formula (VIII), such as for example ΝH3 (or acetic acid ammonium salt), pyrrolidine and the like, in the presence of a suitable solvent, such as for example acetone, tetrahydrofuran, N^tV-dimethylformamide and the like.
Figure imgf000025_0001
(VΗ) (I-e)
Compounds of formula (I) wherein R3 represents CH2-OH, said compounds being represented by formula (I-f), can be prepared by reacting an intermediate of formula (VII) with a suitable reducing agent, such as for example ΝaBH in the presence of a suitable solvent, such as for example tefrahydrofuran.
Figure imgf000025_0002
Compounds of formula (I') can be prepared according to the above described reactions but starting from an intermediate wherein the carbon atom carrying the Rt and t substituent has the (S) configuration.
Alternatively, compounds of formula (I) wherein the carbon atom carrying the Ri and Rt substituent has the (R) configuration can be prepared according to the above described reactions but starting from an intermediate wherein the carbon atom carrying the Ri and R4 substituent has the (R) configuration.
The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions. The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboper- oxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarbo- peroxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. teitbutyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Compounds of formula (I) wherein R3 represents C(=0)-0-Cι.6alkyl, may be converted into a compound of formula (I) wherein R3 represents CH2-OH by reaction with a suitable reducing agent, such as for example LiHBEt3 in the presence of a suitable solvent, such as for example tetrahydrofuran.
Compounds of formula (I) wherein R3 represents C(=O)-0-Cι-6alkyl, can also be converted into a compound of formula (I) wherein R3 represents C(=0)-OH by reaction with a suitable base, such as ΝaOH, in the presence of a suitable solvent, such as for example H20, tetrahydrofuran or an appropriate alcohol, e.g. methanol and the like.
Compounds of formula (I) wherein R3 represents
Figure imgf000026_0001
can also be converted into a compound of formula (I) wherein R3 represents C(=0)-ΝR6aRsb, by reaction with the appropriate base of formula NH saRόb in a suitable solvent, such as for example H2O.
Compounds of formula (I) wherein R3 represents C(=0)-0-H, can be converted into a compound of formula (I) wherein R3 represents
Figure imgf000026_0002
by reaction with the appropriate base of formula NHRgaRόb in the presence of N'-(e1hylcarbonimidoyl)-N,N- dime1hyl-l,3-propanediamine, 1 -hydroxy- lH-benzotriazole and a suitable solvent, such as for example N,N-dimethylformamide.
Compounds of formula (I) wherein R3 represents C(=0)-0-H, can also be converted into a compound of formula (I) wherein R3 represents C(=O)-ΝH by reaction with NH4OH in the presence of SOCl2. Compounds of formula (I) wherein R3 represents C(=0)-0-C gall y 1, can also be converted into a compound of formula (I) wherein R3 represents
Figure imgf000027_0001
by reaction with H0-Cι-6alkyl-0-Cι-6alkyl in the presence of NaBH4.
Compounds of formula (I) wherein R3 represents cyano or C(=0)-0-Cι-6alkyl, can be converted into a compound of formula (I) wherein R3 represents aminocarbonyl by reaction with NH4OH.
Compounds of formula (I) wherein R3 represents cyano, can also be converted into a compound of formula (I) wherein R3 represents
Figure imgf000027_0002
by reaction with hydrogen sulfide in the presence of N-ethyl-N-(l-methylethyl)- 2-propanamine in a suitable solvent such as pyridine.
Compounds of formula (I) wherein R3 represents can be converted into a compound of formula (I) wherein R3 represents
Figure imgf000027_0003
by reaction with chloroCi-βalkyMg in a suitable solvent such as tefrahy&ofuran.
Compounds of formula (I) wherein R3 represents C(=0)-Cι-6alkyl can be converted into compounds of formula (I) wherein R3 represents hydroxyQ-βalkyl by reaction with a suitable reducing agent such as NaBFLt, in the presence of a suitable solvent such as methanol.
Some of the compounds of formula (I) and some of the intermediates in the present in- vention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compound's into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.
Intermediates of formula (II-a) may be prepared by reacting an intermediate of formula (V JI) wherein W3 represents a suitable leaving group, such as for example halo, e.g. bromo, with an intermediate of formula (LX) in the presence of a suitable base, such as for example N,N-diisopropylethanamine, and a suitable solvent, such as for example tetrahydrofuran.
Figure imgf000028_0001
Intermediates of formula (LX) wherein R4 represents hydrogen, said intermediates being represented by formula (LX-a), may be prepared by reacting an intermediate of formula
(X) with a suitable reducing agent, such as for example H2, in the presence of a suitable catalyst, such as for example Raney Nickel, a suitable catalyst poison, such as for example a thiophene solution, and a suitable base, such as for example NH3.
Figure imgf000028_0002
(X) (LX-a)
Intermediates of formula (X) may be prepared by reacting an intermediate of formula
(XI) with HO-NH2 in the presence of a suitable base, such as for example Na2C0 , and a suitable solvent, such as for example an alcohol, e.g. ethanol, and water.
Figure imgf000029_0001
Intermediates of formula (Il-b) can be prepared by reacting an intermediate of formula (VIII) with an intermediate of formula (XII) in the presence of a suitable solvent, such as for example acetonitrile.
Figure imgf000029_0002
(vm) (xπ) (π-b)
Intermediates of formula (XII) can be prepared by reacting an intermediate of formula (XIH) with trimethyloxonium and tetrafluoroborate in the presence of a suitable solvent, such as for example methylenechloride.
Figure imgf000029_0003
Intermediates of formula (XIH) wherein R4 is hydrogen, said intermediates being represented by formula (XlU-a), can be prepared by reacting an intermediate of formula (XTV) with HC(=0)-NH2 in the presence of a suitable acid, such as for example formic acid.
Figure imgf000029_0004
Intermediates of formula (III) can be prepared from an intermediate of formula (XV) in the presence of formic acid or a formate, such as for example n-butylformate, and in the presence of a suitable solvent, such as for example xylene. formic acid or formate
Figure imgf000030_0002
Figure imgf000030_0001
(XV) (IH) Intermediates of formula (XV) can be prepared by reacting an intermediate of formula (IX) with an intermediate of formula (XVI) wherein W4 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, in the presence of a suitable base, such as for example N,N-diethylethanamine, and a suitable solvent, such as for example N,N-dimethylformamide or tetrahydrofuran. The intermediates of formula (IX) may contain a chiral center at the carbon atom carrying the Rj and Rt substituent depending on the substituents representing
Figure imgf000030_0003
and Rt. Said stereospecific intermediates of formula (LX) are represented by formula (LX-b). When the reaction is performed starting from a stereospecific intermediate of formula (LX-b), a stereospecific intermediate of formula (XV) is obtained, said intermediate being represented by formula (XV-a).
Figure imgf000030_0004
(TX) (XVT) (XV)
Figure imgf000030_0005
* indicates the chiral center and may be (R) or (S) depending on the R and R substituents Stereospecific intermediates of formula (XV-a) can also be prepared by reacting an intermediate of formula (XV) with a suitable stereospecific resolution agent, such as for example [S-(R*,R*)]-2,3-bis[(4-methylbenzoyl)oxy]-butanedioic acid, in the presence of a suitable solvent, such as for example an alcohol, e.g. 2-propanol. When a stereospecific intermediate of formula (XV-a) is reacted further according to the methods described hereinabove, the resulting intermediates are also stereospecific and finally the resulting final compounds are also stereospecific.
Intermediates of formula (XV) wherein R4 represents hydrogen, said intermediates being represented by formula (XV-b), can also be prepared by reacting an intermediate of formula (XXVI) with an intermediate of formula (XXVTI) in the presence of a suitable reducing agent, such as for example H2, a suitable catalyst, such as for example Pd on charcoal, a suitable catalyst poison, such as for example a thiophene solution, a suitable weak base, such as for example KF or potassium acetate, a suitable acid, such as for example hydrochloric acid, and a suitable solvent, such as for example an
(XXVT) (XXVTI) (XV-b) Intermediates of formula (LX-b), can be prepared by reacting an intermediate of formula (XVII) with triphenylphosphine, in the presence of a suitable solvent, such as for example tetiahydrofuran and water or by reacting an intermediate of formula (XVII) with a suitable reducing agent, such as for example H2, in the presence of a suitable catalyst, such as for example Pt on charcoal or Pd on charcoal, and a suitable solvent, such as for example an alcohol, e.g. methanol.
Figure imgf000031_0002
* indicates the chiral center and may be (R) or (S) depending on the Ri and R4 substituents When a stereospecific intermediate of formula (TX-b) is reacted further according to the methods described hereinabove, the resulting intermediates are also stereospecific and finally the resulting final compounds are also stereospecific.
Intermediates of formula (XVH) can be prepared by reacting an intermediate of formula (XVIII) with diphenylphosphoryl azide in the presence of 2,3,4,6,7,8,9,10- ortahydro-pyrimido[l,2-a]azepine and in the presence of a suitable solvent, such as for example toluene.
Figure imgf000032_0001
(xvm) (XVII)
* indicates the chiral center and maybe (R) or (S) depending on the and R4 substituents Stereospecific intermediates of formula (XNIII) wherein R4 is hydrogen and Ri is methyl, ethyl, or n-propyl, said Ri being represented by Λlk and said intermediates being represented by formula (XVffl-a) and (XVTII-b), can be prepared by reacting an intermediate of formula (XLX) with ZnAlk2 wherein Alk represents methyl, ethyl or n-propyl, in the presence of a stereospecific catalyst, such as for example N,N'-( 1 R,2R)- 1 ,2-'cyclohexanediylbis [1,1,1 -trifluoro] -methanesulfonamide respectively N T-(l S,2S)- 1 ,2-cycIohexanediylbis[l , 1 ,1 -trifluoro]-methanesulfonamide, Ti(iPrO)4
Figure imgf000032_0002
(X X) lR^R (XViπ-a)
ZnAlk,
Figure imgf000032_0004
Figure imgf000032_0003
Intermediates of formula (V) can be prepared by reacting an intermediate of formula (XX) wherein W5 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, with an intermediate of formula (IX) and an intermediate of formula (XXI), in the presence of a suitable base, such as for example N,N- diisopropylethanamine, and a suitable solvent, such as for example tetrahychofuran.
Figure imgf000033_0001
(V)
Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (XXII) wherein Wβ represents a suitable leaving group, such as for example halo, e.g. chloro, with an intermediate of formula (XXTH) in the presence of a suitable solvent, such as for example tetiahydrofuran, optionally in the presence of a suitable base, such as for example N,N-diethylethanamine.
Figure imgf000033_0002
(xxπ) (XXIH) (VT)
Intermediates of formula (XXII) wherein We represents chloro, said intermediates being represented by formula (XXTJ-a), can be prepared by reacting an intermediate of formula (XXIV) with SOCl2 optionally in the presence of a suitable solvent, such as for example methylene chloride.
Figure imgf000033_0003
(xxrv) (xxn-a)
Intermediates of formula (XXTV) can be prepared by reacting an intermediate of formula (III) with an intermediate of formula (XXVT) in the presence of KSCN, NaOC(CH3)3, a suitable acid, such as for example hydrochloric acid, and a suitable solvent, such as for example tetrahydrofuran. This reaction also leads to the preparation of intermediates of formula (XXV).
Figure imgf000034_0001
(ΩI) (XXVI) (XXTV) (XXV) Intermediates of formula (XXTV) can also be prepared by hydrolyzing an intermediate of formula (XXV) in the presence of a suitable base, such as for example sodium hydroxide, in the presence of a suitable solvent, such as an alcohol, e.g. methanol, and water. Intermediates of formula (XXTV) may also be prepared by hydrolysis of an intermediate of formula (XXV) in the presence of a suitable acid, such as for example trifluoroacetic acid, in the presence of a suitable solvent, such as for example methylene chloride.
In the preparation of the compounds of the present invention, interesting intermediates are intermediates of formula (LX)
Figure imgf000034_0002
OX) a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or stereochemically isomeric form thereof.
As already indicated hereinabove, the intermediates of formula (LX) may contain a chiral center at the carbon atom carrying the Ri and R4 substituent depending on the substituents representing Ri and R«. In case said carbon atom represents a chiral center, a preferred embodiment of the intermediates of formula (IX) are those intermediates wherein the intermediate is stereospecific, i.e. wherein the intermediate has the (R) or (S) configuration at the carbon atom carrying the R] and Rt substituent (intermediates of formula (EX-b). Particularly preferred are those intermediates of formula (LX-b) which have the (S) configuration (intermediates of formula (LX-b-1). Thus the present invention also relates to intermediates of formula (IX-b-1)
Figure imgf000035_0001
(IX-b-1) a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof.
The present invention also relates to intermediates of formula (IX-b-1) provided that when n=2 and each R2 is chloro and said two chloro substituents are placed in meta and para position, then Ri is other than ethyl.
Another preferred embodiment are those intermediates of formula (LX-b- 1 ) wherein each R2 is independently selected from halo,
Figure imgf000035_0002
or polyhaloCi-βalkyl. provided that when n=2 and each R2 is chloro and said two chloro substituents are placed in meta and para position, then Rj is other than ethyl.
A further embodiment are those intermediates of formula (LX-b-1) wherein n is 1, 2, or 3, in particular 2, provided that when n is 2 and each R2 is chloro and said two chloro substituents are placed in meta and para position, then Ri is other than ethyl. . „
Again another embodiment are those intermediates of formula (LX-b-1) wherein n is 2 and the two R2 substituents are placed in meta and para position provided that when each R2 is chloro, then Ri is other than ethyl.
Another embodiment are those intermediates of formula (LX-b-1) as described hereinabove wherein t is hydrogen.
Also interesting are those intermediates of formula (EX) and (LX-b-1) wherein Ri is hydrogen, methyl, ethyl, n-propyl, methoxymethyl, cyclohexyl, cyclopropyl, dimethylaminomethyl, 2-thienyl, 3,4-dichlorophenyl, in particular methyl, ethyl, n-propyl, methoxymethyl, more in particular methyl, ethyl and n-propyl provided that when n is 2 and R2 represents chloro, and said two chloro substituents are placed in meta and para position, and R4 is hydrogen, then Ri is other than ethyl, cyclopropyl phenyl, and provided that when n is 2 and R2 represents chloro, and said two chloro substituents are placed in meta and para position, and R4 is methyl, then Ri is other than methyl and provided that when n is 2 and said two R2 substituents are placed in meta and para position and R2 in meta position is trifluoromethyl and R2 in para position is fluoro, and is hydrogen, then Ri is other than ethyl.
Also interesting are those intermediates of formula (EX) or (EX-b-1) as described hereinabove wherein R2 is chloro, fluoro, or trifluoromethyl, in particular chloro or fluoro, more in particular fluoro.
Particularly interesting intermediates are those intermediates of formula (EX-a) or (IX-b- 1 ) having the following formula
Figure imgf000036_0001
(EX-a-l) (EX-b-l-l) a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof, wherein Alk is defined as hereinabove, i.e. Alk represents methyl, ethyl and n-propyl, and each R2a and R2b independently represents chloro, fluoro or trifluoromethyl.
An interesting embodiment are. those intermediates of formula (EX-a-l) provided that when R2a and R b are both chloro or when R2a is trifluoromethyl and R2b is fluoro, then Alk is other than ethyl.
Further interesting intermediates of formula (EX-a-l) are those intermediates of formula (IX-a-1) provided that when R2a and R2b are both chloro, then Alk is other than methyl, ethyl, n-propyl and provided that when R2a and R2b are both fluoro or R2a is trifluoromethyl and R2b is fluoro or R2a is fluoro and R2b is trifluoromethyl then Alk is other than ethyl.
Also interesting are those intermediates of formula (EX-b-l-l) provided that when R∑a and R2 are both chloro, then Alk is other than ethyl.
A particular interesting intermediate of formula (EX-b-l-l) is that intermediate wherein R2a and R2b are both fluoro and Alk represents ethyl, i.e. a compound of formula (EX-b- 1-1-a).
Figure imgf000037_0001
(EX-b-l -l -a)
The compounds of formula (I) and (V) show CCR2 receptor antagonistic properties.
The C - C chemokine receptor 2 (CCR2) and its ligand monocyte chemoattractant (chemotactic) protein (MCP-1; in new chemokine nomenclature also called CCL2) are recognized to be implicated in both acute and chronic inflammatory processes.
Chemokines (contraction of "chemotactic cytokines") are most important regulators of leukocyte trafficking. This biological role is exerted by interacting - on target cells - with seven-transmembrane-domain receptors that are coupled to heterodimeric G proteins. Chemokines are mainly grouped into 2 major families (C - C or C - X - C family) dependent on the presence of an amino acid (represented by X) between the two conserved cysteine residues (represented by C) near the amino terminus. In general, chemokines from the C - C family attract monocytes, macrophages, T cells and NK cells.
A chemokine, which acts through the CCR2 receptor, is MCP-1 as indicated above. Therefore, the CCR2 receptor is also known as the MCP-1 receptor. MCP-2, MCP-3 and MCP-4 may also act, at least in part, through this receptor.
It is recognized that the CCR2 receptor and MCP-1 play a role in the pathophysiology of various inflammatory diseases. Therefore, CCR2 receptor antagonists, which block the CCR2 receptor, have potential as pharmaceutical agents to combat inflammatory conditions such as arthritis, osteoarthritis, rheumatoid arthritis, glomerulonephritis, diabetic nephropathy, lung fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, vasculitis, hepatitis, nonalcoholic steatohepatitis, inflammatory conditions of the brain such as Alzheimer's disease, restenosis, alveolitis, asthma, allergic rhinitis, allergic conjunctivitis, atherosclerosis, psoriasis, delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease, acute or chronic brain inflammation, e.g. multiple sclerosis, autoimmune encephalomyelitis, chronic obstructive pulmonary disease (COPD), uveitis, dermatitis, atopic dermatitis. CCR2 receptor antagonists may also be useful to treat autoimmune diseases such as diabetes or transplant rejection, stroke, reperfusion injury, ischemia, cancer, myocardial infraction, pain, in particular neuropathic pain.
The compounds of the present invention may also be used to inhibit the entry of Human Immunodeficiency Virus (HTV) into monocytes and lymphocytes, thereby having a therapeutic role in the treatment of AIDS (Acquired Immunodeficiency Syndrome).
The CCR2 receptor exists in two isoforms, namely the CCR2A and the CCR2B receptor.
Due to their CCR2 receptor antagonistic activity, in particular their CCR2B receptor antagonistic activity, the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines, polymoφhic forms or stereochemically isomeric forms are useful in the treatment or prevention, in particular for the treatment, of diseases or conditions mediated through the activation of the CCR2 receptor, in particular the CCR2B receptor. Diseases or conditions related to an activation of the CCR2 receptor comprise inflammatory conditions such as arthritis, osteoarthritis, rheumatoid arthritis, glomerulonephritis, diabetic nephropathy, lung fibrosis, idiopathic pulmonary fibrosis, sarcoidosis, vasculitis, hepatitis, nonalcoholic steatohepatitis, inflammatory conditions of the brain such as Alzheimer's disease, restenosis, alveolitis, asthma, allergic rhinitis, allergic conjunctivitis, atherosclerosis, psoriasis, delayed-type hypersensitivity reactions of the skin, inflammatory bowel disease, acute or chronic brain inflammation, e.g. multiple sclerosis, autoimmune encephalomyelitis, chronic obstructive pulmonary disease (COPD), uveitis, dermatitis, atopic dermatitis, autoimmune diseases such as diabetes or transplant rejection, stroke, reperfusion injury, ischemia, cancer, myocardial infraction, pain (neuropathic pain). In particular, the compounds of formula (I) are useful in the treatment or prevention of inflammatory diseases and autoimmune diseases, especially rheumatoid arthritis, atherosclerosis, multiple sclerosis, inflammatory bowel disease and chronic obstructive pulmonary disease (COPD). The compounds of formula (I) are also of particular interest in the treatment or prevention of psoriasis, asthma, rheumatoid arthritis or pain (neuropathic pain), more in particular psoriasis, asthma or rheumatoid arthritis.
In view of the above-described pharmacological properties, the compounds of formula (I), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms, may be used as a medicine. In particular, the present compounds can be used for the manufacture of a medicament for treating or preventing diseases mediated through activation of the CCR2 receptor, in particular the CCR2B receptor. More in particular, the compounds of the invention can be used for the manufacture of a medicament for treating or preventing inflammatory diseases, especially rheumatoid arthritis, atherosclerosis, multiple sclerosis, inflammatory bowel disease and chronic obstructive pulmonary disease (COPD). The compounds of the invention can also in particular be used for the manufacture of a medicament for treating or preventing psoriasis, asthma, rheumatoid arthritis or pain (neuropathic pain), more in particular psoriasis, asthma or rheumatoid arthritis.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from diseases mediated through activation of the CCR2 receptor, in particular mediated through the CCR2B receptor. Said methods comprise the administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The blockade of the CCR2 receptor by the present compounds of formula (I) inhibits the normal function of MCP-1. Therefore, the present compounds can also be described as MCP-1 inhibitors and hence can be used to prevent or treat diseases mediated through MCP- 1.
The present invention also provides compositions for preventing or treating diseases mediated through activation of the CCR2 receptor, in particular the CCR2B receptor. Said compositions comprise a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
The compounds of the present invention may be formulated into various pharmaceutical forms for administration puφoses. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
The compounds of the present invention may also be topically administered in the form of drops, in particular eye drops. Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the Uke, and segregated multiples thereof.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
The compounds of formula (I) may also be used in combination with other conventional anti-inflammatory or immunosuppressive agents, such as steroids, cyclooxygenase-2 inhibitors, non-steroi<tel-anti-mflammatory drugs, TNF- α antibodies, such as for example acetyl salicylic acid, bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen, naproxen, naproxen sodium, tiaprofen acid, flurbiprofen, mefenamic acid, nifluminic acid, meclofenamate, indomethacin, proglumetacine, ketoprofen, nabumetone, paracetamol, piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, beclomethasone dipropionate, betamethasone, beclamethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, celecoxib, rofecoxib, valdecoxib, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine, antilymphocytory immunoglobulines, antithymocytory immunoglobulines, azathioprine, cyclosporine, tacrolimus substances, ascomycin, rapamycin, muromonab-CD3.
Thus, the present invention also relates to the combination of a compound of formula (I) and another anti-inflammatory or immunosuppressive agent. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula ( , and (b) another anti-inflammatory or immunosuppressive compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases mediated through activation of the CCR2 receptor, in particular mediated through the CCR2B receptor. The different drugs in such products may be combined in a single preparation together with pharmaceutically acceptable carriers. Alternatively, such products may comprise, for example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing another anti-inflammatory or immunosuppressive compound. Such a product may have the advantage that a physician can select on the basis of the diagnosis of the patient to be treated the appropriate amounts of each component and the sequence and timing of the administration thereof.
The following examples are intended to illustrate the present invention.
Experimental Part
Hereinafter "RT" means room temperature, "THF" means tefrahydrofuran, "DIPE" means diisopropylether, "TFA" means trifluoroacetic acid, "DBU" means 2,3,4,6,7,8,9, 10-octahydropyrimido[ 1 ,2-a]azepine and "DMF" means N,N-dimethylformamide.
A. Preparation of the intermediate compounds
Example Al a. Preparation of intermediate 1
Figure imgf000042_0001
A solution of Νa2C03 (part of 0.52 mol) in H20 (150 ml) was added to a stirring mixture of l-(3,4-dichlorophenyl)-l-propanone (0.345 mol) in ethanol, p.a. (150 ml), then the remainder of Na2C03 was added and hydroxylamine monohydrochloride (0.345 mol) was added portionwise while stirring vigorously. The reaction mixture was heated to reflux temperature and extra H20 (75 ml) was added, then the resulting mixture was stirred and refluxed for 6 hours. Extra hydroxylamine monohydrochloride (2.4 g) was added and the mixture was refluxed further for 18 hours. Again extra hydroxylamine monohydrochloride (3 g) was added; the reaction mixture was refluxed for 24 hours and stirred for 2 days at room temperature. The solids were filtered off, washed with EtOH/H20 (1/1) and dried (vacuum, stream of air) at 56°C. Yield: 71.8 g of intermediate 1 (95.4 %). b. Preparation of intermediate 2 and 3
Figure imgf000043_0001
Intermediate 2 Intermediate 3
A mixture of intermediate 1 (0.3 mol) in CH3OH/NH3 (7 N) (500 ml) was hydrogenated at 14°C with Raney Nickel (cat. quant.) as a catalyst in the presence of thiophene solution (6 ml). After uptake of H2 (2 equiv.), the catalyst was filtered off and the filtrate was evaporated, then co-evaporated 2 times with toluene. The residue was stirred in boiling 2-propanol (250 ml) and the mixture was filtered off hot. The filtrate was allowed to reach room temperature and HCl/2-propanol (6N, 150 ml) was added slowly while stirring vigorously. The solvent was evaporated and the residue was stirred in DEPE, then filtered off, washed and dried (vacuum) at 60°C. Yield: 53 g of intermediate 2 (73.4 %). A part of this fraction was converted into its free base: Intermediate 2 (18.0 g) was stirred in CH2C12 (200 ml) and a 15 % aqueous K2C03 solution was added, then the resulting mixture was stirred for 1 hour and a 50 % NaOH solution was added to increase the pH. The organic layer was separated, washed with H20, dried (MgS04), filtered off and the solvent was evaporated. Yield: 51 g of intermediate 3.
Example A2 a. Preparation of intermediate 4
Figure imgf000043_0002
Intermediate 3 (prepared according to Al .b) (0.00208 mol) was dissolved in THF (15 ml) and N-ethyl-N-(l-methylethyl)-2-propanamine (0.0052 mol) was added, followed by l-(2-ammo-4-methyl-5-thiazolyl)-2-bromo-ethanone monohydrobromide (0.00104 mol). The reaction mixture was stirred at room temperature for 18 hours and benzoyl isothiocyanate (0.003 mol) was added, then the mixture was stirred for 2 hours at room temperature and poured out into ice-water (60 ml). The product was extracted with CH2C12 and then the organic layer was separated, dried (MgS04) and filtered off. Finally, the solvent was evaporated. Yield: 1.38 g of intermediate 4. b. Preparation of intermediate 5
Figure imgf000044_0001
Intermediate 3 (prepared according to Al.b) (208 mg) was dissolved in THF, p.a., dried on molecular sieves, (15 ml) and then N-ethyl-N-(l-methylethyl)-2-propanamine (0.0016 mol) was added followed by l-(2-amino-4-methyl-5-thiazolyl)-2-bromo- ethanone monohydrobromide (0.00095 mol). The reaction mixture was stirred for 18 hours at room temperature and the resulting precipitate was filtered off, washed with THF and dried in vacuum. Yield: 330 mg of intermediate 5.
Example A3 a. Preparation of intermediate 6
Figure imgf000044_0002
A solution of l-(3,4-dichlorophenyl)-l-propanone (0.0748 mol) in formamide (45 ml) and formic acid (30 ml) was stirred and refluxed for 22 hours and then the reaction mixture was allowed to reach room temperature. The mixture was warmed to 50°C, poured out into ice water (400 ml) and extracted with EtOAc. The organic layer was separated, washed with H20, with a saturated aqueous ΝaHC03 solution and again with H20 and with brine, then dried (MgS04) and filtered off. The solvent was evaporated and the residual oil was left to stand overnight. The resulting solids were filtered off, stirred in DIPE, filtered off again, washed and dried (vacuum) at 50°C. Yield: 14.0 g of intermediate 6 (80.6 %). b. Preparation of intermediate 7
Figure imgf000044_0003
A solution of intermediate 6 (0.0032 mol) in CH2C12 p.a. (5 ml) was stirred at room temperature under N2 and then a solution of trimethyloxonium tetrafluoroborate (0.00331 mol) in CH2C12 p.a. (5 ml) was added. The reaction mixture was stirred at room temperature for 24 hours and was slowly poured out into an aqueous NaOH solution with ice, then CH2C12 was added. The separated organic layer was dried over NaOH-pellets, filtered off and the solvent was evaporated, yielding intermediate 7 which was used in the next step. c. Preparation of intermediate 8
Figure imgf000045_0001
2-Bromo-l-(3,4-dichlorophenyl)ethanone (0.00284 mol) was added to a stirring solution of intermediate 7 (0.00569 mol) in dry CH3CN, p.a. (35 ml) under N2 and then the solution was stirred and refluxed for 24 hours. The reaction mixture was left to stand over the weekend and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent gradient: CH2Cl2/CH3OH 100/0 ->
99.5/0.5 -> 99/1). The product fractions were collected and the solvent was evaporated. Yield: 1.1 g of fraction 1. A part (0.55 g) of this fraction was purified by reversed phase high-performance Uquid chromatography (CH3CN). The product fractions were collected and the organic solvent was evaporated. The aqueous concentrate was extracted with CH2C12 and the separated organic layer was evaporated. Yield: 0.12 g of intermediate 8.
Example Λ4 a. Preparation of intermediate 9
Figure imgf000045_0002
A solution of intermediate 2 (prepared according to Al.b) (0.0748 mol) and chloro acetic acid methyl ester (0.08 mol) in DMF, p.a., dried on molecular sieves, (150 ml) was stirred at room temperature under N and Et3N (0.224 mol) was slowly added, then the reaction mixture was stirred for 20 hours at room temperature and extra chloro acetic acid methyl ester (3.3 ml) was added. The mixture was stirred for another 20 hours at room temperature and again extra chloro acetic acid methyl ester (2 ml) was added. The resulting mixture was stirred for 24 hours and then the solids were filtered off and washed with DMF. Et20 (800 ml) was added and the mixture was washed 3 times with H20 (500 ml). The organic layer was separated, dried (MgS04), filtered off and the solvent was evaporated, then co-evaporated with toluene. The residual oil (23.4 g) was filtered over silica gel (eluent: CH2C12/CH30H 99/1). The product fractions were collected and the solvent was evaporated, finally co-evaporated with toluene. Yield: 20.6 g of intermediate 9 (99.7 %). b. Preparation of intermediate 10
Figure imgf000045_0003
A solution of formic acid (7.5 ml) and intermediate 9 (0.0746 mol) in xylene, p.a. (225 ml) was stirred and refluxed for 4 hours and then the reaction mixture was allowed to reach room temperature. The mixture was washed 2 times with H20 (2 x 200 ml), with a saturated aqueous NaHC03 solution (200 ml) and with brine (200 ml), then the separated organic layer was dried (MgSO ) and filtered off. Finally, the solvent was evaporated. Yield: 21.3 g of intermediate 10 (93.9 %)
Example Λ5 a. Preparation of intermediate 11 and 20
Figure imgf000046_0001
(S) (-) <*> <+> Intermediate 11 intermediate 20
A mixture of N,N'-(lR,2R)-l,2-cyclohexanediylbis[l,l,l- trifluoromethanesulfonamide] (0.005 mol) and Ti(i-PrO)4 (0.030 mol) in toluene (q.s.) was degassed and placed under Λr-flow, then the reaction mixture was stirred for 20 minutes at 40°C and cooled to -78°C. Et2Zn (0.030 mol) was added dropwise and after
20 minutes, a mixture of 3,4-dichlorobenzaldehyde (0.0250 mol) in toluene (q.s.) was added dropwise. The reaction mixture was allowed to reach 0°C. The mixture was stirred overnight at room temperature, then quenched with HCl (2Ν). This mixture was extracted with CH2C12. The separated organic layer was washed, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent CH2C12 /CH30H 98/2). The product fractions were collected and the solvent was evaporated. Yield: 5.1 g of intermediate 11.
Intermediate 20 can be prepared by the above reaction by using N,N'-(l S,2S)-1,2- cyclohexanediylbis[ 1,1,1 -trifluoromethanesulfonamide] as catalyst. b-1 . Preparation of intermediate 12
Figure imgf000046_0002
(R)
A mixture of intermediate 11 (0.025 mol; prepared according to A5.a) and diphenylphosphoryl azide (0.030 mol) in toluene (50 ml) was stirred at 0°C and 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (0.030 mol) was added. The reaction mixture was stirred for 2 hours at 0°C, then stirred overnight at room temperature. The mixture was diluted with water and toluene. The organic layer was separated, washed once with water, once with 5% HCl, and the solvent was evaporated, yielding intermediate 12 (quantitative yield; used in next reaction step). b-2). Preparation of intermediate 21
Figure imgf000047_0001
(S)
A mixture of intermediate 20 (prepared according to A5.a) (0.127 mol) and diphenylphosphoryl azide (0.153 mol) in toluene (q.s.) was stirred at 0°C. 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine (0.153 mol) was added dropwise and the reaction mixture was stirred for 1 hour at 0°C, then for 2 hours at room temperature, then for 3 hours at 50°C. The reaction mixture was cooled, washed with water, with 0.5 M HCl, with water, dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2/CH3θH 99.5/0.5). The product fractions were collected and the solvent was evaporated. Yield: 23.5 g of intermediate 21. c-1. Preparation of intermediate 13 ^ι " T ™2 (R) A mixture of intermediate 12 (0.025 mol; prepared according to Λ5.b- 1 ), triphenylphosphine (0.027 mol) in THF (70 ml) and H20 (20 ml) was stirred overnight at room temperature. The solvent was evaporated The residue was treated with 1 % HCl. The acidic layer was washed witivDIPE, then alkalized, followed by an extraction with CH2C12. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over siUca gel. The product fractions were collected and the solvent was evaporated. Yield: 1.1 g of intermediate 13. c-2. Preparation of intermediate 22
Figure imgf000047_0002
(S) A mixture of intermediate 21 (prepared according to Λ5.b-2) (0.122 mol; 23.5 g) in methanol (q.s.) was hydrogenated at 50°C with PfC 5% (5 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated. Yield: 21 g of intermediate 22. d. Preparation of intermediate 14
Figure imgf000047_0003
A solution of intermediate 3 (prepared according to Al.b) (0.0116 mol) in Et3N (0.013 mol) and DMF, p.a., dried on molecular sieves, (20 ml) was stirred on an ice bath. A solution of chloro acetonitrile (0.0128 mol) in DMF, p.a., dried on molecular sieves, (2.5ml) was added dropwise. The reaction mixture was stirred at room temperature for 6 hours. More chloro acetonitrile (0.0063 mol) in DMF, p.a., dried on molecular sieves, (1 ml) was added dropwise. The reaction mixture was stirred for another 24 hours. More chloro acetonitrile (0.0063 mol) in DMF, p.a, dried on molecular sieves, (1 ml) was added dropwise and the reaction mixture was stirred for another 24 hours. More Et3N (1 ml) was added, then more chloro acetonitrile (0.0079 mol) in DMF, p.a., dried on molecular sieves, (1 ml) was added dropwise. The reaction mixture was stirred for 20 hours. The precipitate was filtered off. The filtrate was poured out into Et20 (200 ml) and washed with H20/NaHC03 (10 %;100 ml) and H20 (2x). The separated organic layer was dried (MgS04), filtered and the solvent was evaporated and co-evaporated with toluene. The residue was purified over silica gel (eluent : CH2Cl2/MeOH 99: 1 ). The desired fractions were collected and the solvent was evaporated and coevaporated with toluene. Yield : 2.3g of intermediate 14 (81.6%). e. Preparation of intermediate 15
Figure imgf000048_0001
A mixture of intermediate 14 (0.00946 mol) and n-butyl formate (15 ml) was stirred and refluxed for 4 days. The solvent was evaporated, then co-evaporated with toluene. Yield: 2.68 g of intermediate 15. Example A6 a. Preparation of intermediate 16 and 17
Figure imgf000048_0002
A solution of intermediate 10 (prepared according to A4.b) (0.0618 mol) and dimethyl ethanedioic acid ester (0.11 mol) in THF,ρ.a., dried on molecular sieves, (100 ml) was stirred under N2-atmosphere, then 2-mefhyl-2-propanol sodium salt (0.066 mol) was added and the reaction mixture was stirred at room temperature for 18 hours and another 24 hours. Finally the mixture was stirred at 60°C for 4 hours. Extra 2-mefhyl- 2-propanol sodium salt (4 g) and extra dimethyl ethanedioic acid ester (6 g) were added and the reaction mixture was stirred over the weekend at room temperature. The solvent was evaporated, the residue was dissolved in H20 (250 ml) and washed 2 times with Et20. The aqueous layer was separated and CH3OH (200 ml), potassium thiocyanic acid salt (10 g) and HCl (36%, p.a.) (q.s.) were added, then the mixture was stirred for 18 hours at 60°C. The solvent was partly evaporated and the concentrate was extracted with CH2C12. The organic layer was separated, dried (MgS0 ), filtered and the solvent was evaporated. The residue (5 g) was purified by filtration over silica gel (eluent: CH2Cl2/CH3OH 99/1). The product fractions were collected and the solvent was evaporated. The residue was triturated under Hexane, filtered off, washed , then dried (vacuum, 50°C). Yield: 5.2 g of intermediate 16. The fractions containing a side-product were combined and the solvent was evaporated, then co-evaporated with hexane DIPE. The residue was stirred in Et20/Hexane and the resulting precipitate was filtered off, washed with hexane, then dried (vacuum, 50°C). Yield: 0.28 g of intermediate 17. b. Preparation of intermediate 18
Figure imgf000049_0001
A mixture of intermediate 17 (0.000257 mol) in thionyl chloride (5 ml) was stirred overnight at room temperature, then the solvent was evaporated and co-evaporated with toluene (p.a.), yielding intermediate 18 used in the next step. c. Preparation of intermediate 19
Figure imgf000049_0002
A solution of intermediate 18 (0.000257 mol) in THF,p.a., dried on molecular sieves, (10 ml) was stirred under N2 and then hydrazinecarboxaldehyde (0.0125 mol) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was evaporated. The residue was stirred in H20 (10 ml) and CH2C12/CH30H (15 ml, 95/5). The organic layer was separated, washed with HCl (IN), dried (MgS04), filtered off and the solvent was evaporated, then co-evaporated with toluene. Yield: 800 mg of intermediate 19.
Example Λ7 a- 1. Preparation of intermediate 24
Figure imgf000050_0001
A mixture
Figure imgf000050_0002
(intermediate 23 prepared according to Λ6.a) (0.0015 mol) and IN NaOH (0.030 mol) in H20 (20 ml) and methanol (50 ml) was stirred for 20 hours at room temperature, then extra IN NaOH (10 ml) was added and the reaction mixture was stirred for 5 hours at room temperature. Half of the solvent was evaporated and IN HCl (40 ml) was added and the precipitated product was extracted with CH2C12. The organic layer was separated, dried, filtered off and the solvent was evaporated. Yield: 5.6 g of intermediate 24. a-2. Preparation of intermediate 28
Figure imgf000050_0003
A mixture of
Figure imgf000050_0004
(intermediate 27 prepared according to A6.a)
(0.0012 mol) in TFA (2 ml) and CH2C12 (70 ml) was stirred for 1 day at room temperature and then the reaction mixture was concentrated, yielding intermediate 28. b. Preparation of intermediate 25
Figure imgf000050_0005
A mixture of intermediate 24 (prepared according to A7.a-1) (0.0075 mol) and SOCl2 (0.015 mol) in CH2C12 (50 ml) was stirred and refluxed on an oil bath for 3 hours and then the solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated again. Yield: 2.9 g of intermediate 25. c. Preparation of intermediate 26
Figure imgf000051_0001
A mixture of hydrazide acetic acid (0.011 mol) and Et3N (0.015 mol) in THF (30 ml) was stirred and cooled on an ice bath at 0-5°C and then a mixture of intermediate 25 (prepared according to A7.b) (0.0075 mol) in THF (20 ml) was added dropwise over 30 minutes at 0-5°C. The reaction mixture was stirred for 1 hour at 0-5°C and then H20 was added and the mixture was extracted with CH2C12. The organic layer was separated, dried, filtered off and the solvent was evaporated. The obtained residue was filtered over silica gel (eluent: CH2CVCH3OH 97/3), then the product fractions were collected and the solvent was evaporated. Yield: 1.25 g of intermediate 26.
Example A8 a. Preparation of intermediate 30
Figure imgf000051_0002
(R) A solution of N,N'-(l S,2S)- 1 ,2-cyclohexanediylbis[l ,1,1 -trifluoromethanesulfonamide] (catalytic quantity) and tetrakis(2-propanolato)titanium (0.415 mol) in toluene (p.a) (500 ml) was degassed under Argon and then stirred for 20 minutes at 1 40 °C. This mixture was cooled on a 2-propanol Cθ2 bath to -78 °C and diethylzinc (0.415 mol) was added dropwise over 15 minutes. The resulting mixture was stirred for 15 minutes at -78 °C and then a solution of 3,4-difluorobenzaldehyde (0.345 mol) in toluene (p.a.) (q.s.) was added dropwise over 20 minutes. The reaction mixture was stirred further for 30 minutes at -78 °C and was then allowed to slowly reach 0 °C. The mixture was quenched with IN HCl and extracted with CH2C12. Both organic layer and aqueous layer were filtered over dicalite and the organic layer in the obtained filtrate was separated, then washed with H20, dried (MgS0 ) and filtered off. FinaUy, the solvent was evaporated. Yield: 57.7 g of intermediate 30. b. Preparation of intermediate 31
Figure imgf000052_0001
A solution of intermediate 30 (0.331 mol) and diphenylphosphoryl azide (0.4 mol) in toluene (p.a.) (500 ml) was stirred under N2 on an ice bath at 0 °C, then DBU (0.4 mol) was added dropwise and the reaction mixture was stirred for 1 hour at 0 °C. The mixture was allowed to reach room temperature and was then stirred for 1 hour at 45 °C and overnight at room temperature. The resulting mixture was poured out into H20 (500 ml) and extracted with Et20 (500 ml). The organic layer was separated, dried (MgS0 ), filtered off and the solvent was evaporated. The residue was filtered over silica gel (eluent: CH2C12 100 %). The product fractions were collected and then the solvent was evaporated and co-evaporated with Toluene. Yield: 57.2 g of intermediate 31. c. Preparation of intermediate 32
Figure imgf000052_0002
A mixture of intermediate 31 (0.29 mol) in CH3OH (600 ml) was hydrogenated with Pd/C 10% (2 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in CH2C12 (300 ml) and then IN HCl was slowly added while the solution was stirred vigorously on an ice bath. After this extraction, the aqueous layer was alkalised with a 50 % NaOH solution to pH > 10 and the resulting mixture was extracted with CH2C12. The organic layer was separated, dried (MgS0 ), filtered off and the solvent was evaporated. Yield: 40.0 g of intermediate 32. d. Preparation of intermediate 33
Figure imgf000052_0003
(S) Brome acetic acid methyl ester (0.28 mol) was added to a stirring solution of intermediate 32 (0.233 mol) and N-ethyl-N-(l -methylethyl)-2-propanamine (0.466 mol) in THF (350 ml) and the reaction mixture was stirred for 5 days at room temperature. The resulting precipitate was filtered off, washed with THF and then the filtrate was evaporated. The obtained residue was stirred in CH2C12 and then washed with a half saturated aqueous NaHC03 solution and with water. The organic layer was separated, dried (MgS0 ), filtered off and then the solvent was evaporated and co-evaporated with toluene. Yield: intermediate 33. e. Preparation of intermediate 34
Figure imgf000053_0001
(S) Formic acid (23 ml) was added to a stirring solution of intermediate 33 (0.23 mol) in xylene (p.a) (400 ml), then the reaction mixture was stirred and refluxed for 4 hours with a Dean-Stark apparatus. The mixture was allowed to reach room temperature and the solvent was evaporated. The residue was filtered over silica gel (eluent: CH2Cl2/CH3OH 99/1). The product fractions with a purity > 95 % were collected and then the solvent was evaporated and co-evaporated with toluene. Yield: 15.2 g of intermediate 34.
Example A9 a. Preparation of intermediate 35
Figure imgf000053_0002
FoUowing procedure was done 3 x. [A mixture of l-(3,4-difluorophenyl)-l-propanone (0.43 mol), glycine methyl ester, hydrochloride (0.5 mol) and KF (0.43 mol) in CH3OH (700 ml) was hydrogenated at 50 °C (in Parr apparatus) with Pd/C 10% (5 g) as a catalyst in the presence of thiophene solution (2 ml). After uptake of H2 (1 equivalent) was complete, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in water, men treated with NaHC03 (q.s.) and the product was extracted with CH2C12. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was dissolved in 2-propanol (1000 ml) and converted into the hydrochloric acid salt with 6 N HCl/2-propanol. The precipitate was filtered off, washed with DIPE (to remove the 2-propanol), then stirred in water. CH2C12 was added and the mixture was treated with K2C03 (q.s.). The layers were separated. The organic layer was dried, filtered and the solvent evaporated.] Yield: 221 g of intermediate 35. b. Preparation of intermediate 36
Figure imgf000054_0001
.[S-(R*^*)]-2,3-bis[(4-methylbenzoyl)oxy] butanedioic acid
A mixture of intermediate 35 (0.9 mol) in 2-propanol (1500 ml) was stirred at room temperature. [S-(R*,R*)]-2,3-bis[(4-methylbenzoyl)oxy]-butanedioic acid (0.9 mol) was added in one portion. The reaction mixture was stirred for 2 hours at room temperature. The precipitate was filtered off and dissolved in refluxing 2-propanol
(1500 ml). Then the mixture was stirred at room temperature, allowing the compound to precipitate again. The precipitate was filtered off, then re-dissolved in boiling 2- propanol. The mixture was allowed to cool to room temperature and the resulting intermediate 36 (96% (S)).
Figure imgf000054_0002
Intermediate 36 (370 g, 0.588 mol) was converted into the free base upon addition of NH4OH/CH2CI2. The product was extracted to give free base residue A*. A mixture of A* (132 g, 0.543 mol) in formic acid (150 ml) and xylene (750 ml) was stirred and refluxed for 5 hours at 120 °C. The solvent was evaporated. The residue was stirred in water, treated with NaHC03 and then the product was extracted with CH C12. The organic layer was separated, dried, filtered and the solvent evaporated. Yield: 146 g of intermediate 37 used in next reaction step, without further purification).
Table 1 lists intermediates of formula (IX) which can be prepared according to one of the above
Figure imgf000054_0003
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0002
B. Preparation of the final compounds Example Bl Preparation of compound 1
Figure imgf000058_0001
1N NaOH (0.006 mol) was added to a solution of intermediate 4 (prepared according to A2.a) (0.0026 mol) in ethanol, p.a. (10 ml), then the solution was stirred at 50°C for 1 hour and was allowed to reach room temperature. The reaction mixture was poured out into H20 (30 ml) and IN HCl (7 ml) was slowly added. The resulting precipitate was filtered off, washed with H20 and dried (vacuum) at 60°C. A part (0.68 g of 0.78 g) of the crude product was purified by high-performance liquid chromatography (eluent: (0.5 % NH4OΛC in H20)/CH3CN 90/10). The product fractions were collected and the organic solvent was evaporated. The aqueous concentrate was extracted with CH2C12, then the organic layer was separated, dried (MgS04) and filtered off. Finally, the solvent was evaporated. Yield: 0.24 g of compound 1.
Example B2 a. Preparation of compound 2
Figure imgf000059_0001
A solution of potassium thiocyanic acid salt (0.00285 mol) in H2O (10 ml) was added to a stirring solution of intermediate 5 (prepared according to A2.b) (0.00095 mol) in methanol (10 ml), then 36% HCl, p. * (0.00475 mol) was added and the reaction mixture was stirred for 4 hours at 55°C. Extra potassium thiocyanic acid salt (0.1 g) was added and the mixture was stirred for 18 hours at 55°C. The resulting mixture was allowed to reach room temperature and was left to stand for 1 hour. The formed precipitate was filtered off, washed with CH30H H20 (1/1) and dried (vacuum) at 60°C. Yield: 0.16 g of compound 2 (m.p.: 301.8-303.3°C) b-1. Preparation of compound 3
Figure imgf000059_0002
H20 (2.5 ml), followed by potassium thiocyanic acid salt (0.00328 mol) and then concentrated HCl (0.5 ml) were added to a solution of intermediate 8 (prepared according to A3.c) (0.0013 mol) in methanol (15 ml) and the reaction mixture was stirred at room temperature for 20 hours, then the mixture was stirred at 55°C for 48 hours and extra concentrated HCl (0.75 ml) was added. The resulting mixture was stirred at 60°C for 24 hours, H20 was added and the mixture was extracted with CH2C12. The organic layer was separated, dried (MgS04), filtered off and the solvent was evaporated. The residue was purified by reversed phase high-performance liquid chromatography (NHtOAc 10 % CH3CN). The product fractions were collected and half of the solvent was evaporated The resulting precipitate was washed with H20 and dried (vacuum) at 50°C. Yield: 0. b-2. Preparation of compound 4
Figure imgf000060_0001
Potassium HCl, IN (0.00086 mol) were
added to a
Figure imgf000060_0002
according to A3. c) (0.000286 mol) in methanol, p.a. (3 ml) and the reaction rnixture was stirred at room temperature for 4 hours. HCl (0.5 ml, concentrated) was added and the mixture was stirred at 55°C for 18 hours, then extra potassium thiocyanic acid salt (0.000515 mol) was added and the reaction rnixture was stirred at 55°C for 7 hours. The mixture was left to stand for 18 hours, H20 (15 ml) was added and the product was extracted with CH2C12. The organic layer was separated and evaporated. The residue was purified by Fast high- performance liquid chromatography using the Reversed Phase-method. The product fractions were collected and the organic volatiles were evaporated. The product was extracted with CH2C12 and the separated organic layer was evaporated. Yield: 0.005 g of compound 4.
Example B3 a. Preparation of compound 5
Figure imgf000060_0003
Intermediate 10 (prepared according to A4.b) (0.002 mol) was added at 0°C to a mixture of N-(l-methylethyl)-2-propanamine lithium salt (0.0025 mol) in THF (40 ml) for 30 minutes and 3,4-dichlorobenzoyl chloride (0.0033 mol) was added then the reaction mixture was reacted for 1 hour and quenched with water. The mixture was extracted with EtOAc, dried and the solvent was evaporated. The residue was diluted with CH3OH and then concentrated HCl (q.s.) and potassium thiocyanic acid salt (1 g) were added. The resulting mixture was heated at 70°C for 48 hours and partitioned between water and CH2C12. The organic layer was separated dried and the solvent was evaporated. The residue was purified by high-performance liquid chromatography. The product fractions were collected and the solvent was evaporated. Yield: 0.180 g of compound 5. b. Preparation of compound 6 Method 1
Figure imgf000061_0001
Intermediate 10 (prepared according to A4.b) (0.003 mol, in 10 ml THF) was added dropwise to a cold (-78°C) solution of N-(l-methylethyl)-2-propanamine lithium salt (0.0036 mol, 2M in THF) in THF (5 ml). After 30 minutes 2-thioρhenecarbonyl chloride (0.0031 mol) was added and the reaction rnixture stood for 1 hour. The rnixture was quenched with ΝH4C1 and extracted with EtOAc. The organic layer was separated, dried (MgS0 ), filtered off and the solvent was evaporated. The residue was diluted with methanol (25 ml), then potassium thiocyanic acid salt (1 g) and concentrated HCl (1 ml) were added The resulting mixture was heated overnight at 70°C and the solvent was evaporated. The residue was partitioned between EtOAc and water, then the separated organic layer was dried and the solvent was evaporated. The residue was purified by high-performance liquid chromatography; the product fractions were collected and the solvent was evaporated. Yield: 0.040 g of compound 6. c. Preparation of compound 6 Method 2
Figure imgf000061_0002
t-BuONa (0.150 g) was added at 0°C to a mixture of intermediate 10 (prepared according to A4.b) (0.00082 mol) in THF (5 ml), then 2-thiophenecarbonyl chloride (0.001 mol) was added and after 30 minutes potassium thiocyanic acid salt (0.250 g) and concentrated HCl (1 ml) were added. The reaction mixture was heated at 70°C for 18 hours and treated with water/CH2Cl2. The organic layer was separated, dried (MgS04), filtered off and the solvent was evaporated. The residue was purified by high-performance liquid chromatography, then the product fractions were collected and the solvent was evaporated. The residue was further purified by Flash column chromatography and then by normal phase high-performance liquid chromatography. The product fractions were collected and the solvent was evaporated. Yield: 45 mg of compound 6. d-1. Preparation of compound 7
Figure imgf000062_0001
N-(l-methylethyl)-2-propanamine lithium salt
dropwise at -78°C under Ν2 to a cold mixture
Figure imgf000062_0002
(prepared according to A4.b) (0.00924 mol) in THF (q.s.). After 30 minutes 5- isoxazolecarbonyl chloride (0.0110 mol) was added and then the reaction mixture was allowed to slowly reach room temperature. The mixture was quenched with NH4CI and the solvent was evaporated. The residue was diluted with CH3OH, with H20 and then potassium thiocyanic acid salt (3 g) and concentrated HCl were added. The reaction mixture was heated overnight at 80°C, then cooled quenched with K2C03 and extracted with CH2C12. The organic layer was separated dried and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2C12/CH30H 100/0 -> 90/10). Two product fractions were collected and the solvent was evaporated to give Residue (I) and Residue (IT). Residue (I) was purified by reversed phase high-performance liquid chromatography. The product fractions were collected and the solvent was evaporated. The residue was diluted with CH2C12 and washed 3 times with IN HCl. The organic layer was separated dried and the solvent was evaporated. Yield: 0.290 g of compound 7. d-2. Preparation of compound 43
Figure imgf000063_0001
A solution of intermediate 34 (prepared according to A8.e) (0.0169 mol) in THF, p.a., dried on molecular sieves (80 ml) was stirred under N2 on a 2-propanol/C02 cooling bath, thenN-(l-methylethyl)-2-propanamine lithium salt (0.0179 mol; 2 M in THF/Heptane) was slowly added dropwise at -78 °C and the mixture was further stirred for 5 minutes. A solution of 5-isoxazolecarbonylchloride (0.02 mol) in THF, p.a., dried on molecular sieves (5 ml) was slowly added dropwise and the resulting mixture was stirred for 90 minutes at -78 °C and was then allowed to reach 10 °C. A solution of KSCΝ (0.051 mol) in H20 (30 ml) was added followed by addition of CH3OH (40 ml) and then concentrated HCl (14 ml). The reaction mixture was stirred for 4 hours at 60 °C and for 18 hours at 70 °C, then the mixture was allowed to reach room temperature. The mixture was poured out into H20 and was extracted with CH2C12. The organic layer was separated dried (MgS04), filtered off and the solvent was evaporated. The residue was purified by high-performance Uquid chromatography (Reversed Phase-method "NHtOAc 10 % CH3CΝ - CH3OH"). The product fractions were collected then the organic solvent was evaporated and the aqueous concentrate was extracted with-CH2Cl2. The organic layer was separated dried (MgS0 ), filtered' off and the solvent was evaporated. Yield: 0.269 g of final compound 43. d-3. Preparation of compound 53
Figure imgf000063_0002
A mixture of intermediate 37 (prepared according to Λ9.c) (0.54 mol) in THF (1000 ml) was stirred and cooled to -78 °C on a C02/2-propanol-bath. 5-Isoxazolecarbonyl chloride (0.75 mol) was added. Then, 1,1,1 -trimethyl-N-(trimethylsilyl)-silanamine Uthium salt, lM/THF (0.8 mol, 800 ml) was added over a 30 minutes period. The mixture was stirred for 4 hours at -78 °C. Then, the reaction temperature was raised to -20 °C. A solution of HCl, concentrated (66 ml) in water (400 ml) was added dropwise over 15 minutes. The organic solvent (THF) was evaporated. Water (400 ml) was added. Then, HCl, concentrated (280 ml) was added followed by methanol (800 ml), then KSCΝ (0.8 mol). The reaction mixture was stirred for 22 hours at 60 °C. Water was added. The mixture was cooled to room temperature, then treated with K2C03 and NaHC03. This mixture was extracted with CH2C12. The separated organic layer was dried filtered and the solvent evaporated. The residue (± 200 g) was purified by high- performance liquid chromatography. The product fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE (2 x). The precipitate was filtered off and dried. Yield: 45.5 g of final compound 53 (rap: 128.5 °C).
Example B4
Preparation of compound 8
Figure imgf000064_0001
A solution of intermediate 15 (prepared according to A5.e) (0.00369 mol) in THF, p.a., dried on molecular sieves, (20 ml) was stirred on a 2-propanol/CO2 cooling-bath and then N-(l-methylethyl)-2-propanamine lithium salt (0.0074 mol) was slowly added at -78°C. The resulting mixture was stirred for 15 minutes and 5-isoxazolecarbonyl chloride (0.0037 mol) was slowly added. The mixture was stirred for 10 minutes at -78°C and was then allowed to reach room temperature. A solution of potassium thiocyanic acid salt (0.011 mol) in H20 (15 ml) was added foUowed by CH3OH (10 ml) and then 36% HCl (1.3 ml). The reaction mixture was stirred for 4 hours at 60°C, poured out into ice-water and extracted with CH2Cl2/CH3OH (98/2). The organic layer was separated dried (MgS04), filtered off and the solvent was evaporated The residue was purified by reversed phase high-performance liquid chromatography (eluent: (0.5 % ΝH4OAc in H20)/CH3CΝ 10/90). The product fractions were collected and the organic solvent was evaporated The aqueous residue was purified by Flash column chromatography on flash tubes (eluent: CH2C12/THF 92/8). The product fractions were collected stirred in CH2Cl2/CH3OH (98/2) and filtered to remove the silica Finally, the filtrate was evaporated. Yield: 0.020 g of compound 8. Example B5
Preparation of compound 9
Figure imgf000065_0001
A solution of intermediate 19 (prepared according to A6.c) (0.00025 mol) in phosphorus oxychloride (5 ml) was stirred at 60°C for 18 hours and then the solvent was evaporated. The residue was stirred in ice-water and extracted with CH2C12. The organic layer was separated dried (MgS04), filtered off and the solvent was evaporated. The residue was stirred in 2-propanone (5 ml) and the mixture was treated with S02-gas for 15 minutes. The solvent was evaporated and the residue was purified by high-performance liquid chromatography. The product fractions were collected and the organic solvent was evaporated The aqueous concentrate was extracted with CH2C12; the organic layer was separated dried (MgS0 ), filtered off and the solvent was evaporated. Yield: 0.010 g of compound 9.
Example B6
Preparation of compound 10
Figure imgf000065_0002
A mixture of compound 5 (prepared according to B3.a) (0.00025 mol) in IN NaOH (1 ml) and methanol (3 ml) was reacted overnight at 70°C and then the solvent was evaporated. The residue was treated with HCl and the mixture was filtered then the desired product was dried (vacuum oven). Yield: 0.070 g of compound 10.
Example B7 a Preparation of compound 11
Figure imgf000065_0003
A mixture of compound 10 (prepared according to B6) (0.00015 mol) in SOCl2 (5 ml) was heated at 70°C for 4 hours, then the reaction mixture was cooled and the solvent was evaporated. The residue was diluted in THF and aqueous NH OH (3 ml) was added in one portion. The reaction mixture was stirred for 15 minutes and the solvent was evaporated. The residue was extracted with CH2C12 and then the organic layer was dried and the solvent was evaporated The residue was taken up in 2-propanone and S02 (gas) was bubbled through the mixture for 10 minutes. The solvent was evaporated and the residue was purified by flash column chromatography (eluent: CH2C12/CH3CN 95/5). The product fractions were collected and the solvent was evaporated. Yield: 15 mg of compound 11. b. Preparation of compound 13
Figure imgf000066_0001
A mixture of compound 12 (prepared according to B6) (0.0012 mol), N'-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine (0.0013 mol) and 1 -hydroxy- /H-benzotriazole (0.0013 mol) in DMF (8 ml) was stirred for 30 minutes at room temperature, then ΝΗ3 (gas) was passed through the solution for 15 minutes and the reaction mixture was stirred for 1 hour. The solvent was evaporated and the obtained residue was stirred in H20, then the mixture was extracted with CH2C12. The organic layer was separated dried filtered off and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure product fractions were collected and the solvent was evaporated. The residue was stirred in DIPE and the resulting solids were collected. Yield: 0.190 g. This fraction was purified by reversed-phase high-performance liquid chromatography, then the pure product fractions were collected and the solvent was evaporated. The obtained residue was stirred in DEPE and then the desired product was filtered off and dried. Yield: 0.091 g of compound 13 (m.p.: 228-229°C).
Example B8
Preparation of compound 14
Figure imgf000066_0002
A mixture of compound 12 (prepared according to B6) (0.0012 mol), N'- (ethylcarbonimidoyl)-N,N-dimethyl-l,3-propanediamine (0.0012 mol) and 1-hydroxy- /H-benzotriazole (0.0012 mol) in DMF (8 ml) was stirred for 30 minutes at room temperature, then 2-aminoethanol (0.0024 mol) was added and the reaction mixture was stirred for 3 hours at room temperature. The solvent was evaporated and the obtained residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure product fractions were collected and the solvent was evaporated. The residue was stirred in DEPE and then the resulting solids were filtered off and dried. Yield: 0.155 g of compound 14 (m.p.: 165-166°C).
Example B9
Preparation of compound 16
Figure imgf000067_0001
A mixture of compound 15 (prepared according to B3) (0.00029 mol) and ΝaBH (0.00211 mol) in 2-methoxyethanol (5 ml) was heated for 24 hours at 100°C and then the solvent was evaporated. The residue was purified by reversed-phase high- performance liquid chromatography. The product fractions were collected and the solvent was evaporated Yield: 0.020 g of compound 16.
Example B10
Preparation of compound 50
Figure imgf000067_0002
A mixture of intermediate 26 (prepared according to A7.c) (0.00125 mol) and Burgess'reagent (0.00375 mol) in THF ( 10 ml) was stirred for 3 hours at room temperature, then CH2C12 was added and the mixture was washed with H20. The organic layer was separated dried filtered off and the solvent was evaporated The obtained residue was filtered over silica gel (eluent: CH2CI2/CH3OH 98/2), then the product fractions were collected and the solvent was evaporated. The residue was stirred in DIPE and the desired product was filtered off and dried. Yield: 0.082 g of final compound 50 (m.p.: 102.8-102.9°C). Tables 2 and 3 list the compounds of formula (I) which were prepared according to one of the above samples (Ex. No.)
Table 2
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0002
Table 3
Figure imgf000070_0001
Figure imgf000070_0003
Figure imgf000071_0001
[ D : [«]20 at concentration of 0.5 g 100 g in CHC13;
C. Analytical Part
LCMS conditions 1
The HPLC gradient was supplied by a Waters Alliance HT 2790 system with a columnheater set at 40°C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on a Xterra MS Cl 8 column (3.5 μm, 4.6 x 100 mm) (12 minutes column) with a flow rate of 1.6 ml/minutes. Three mobile phases (mobile phase A : 95% 25mM ammoniumacetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50% B and 50% C in 6.5 minutes, to 100 % B in 1 minute, 100% B for 1 minute and reequilibrate with 100 % A for 1.5 minute. An injection volume of 10 μL was used.
Mass spectra were acquired by scanning from 100 to 1000 in Is using a dwell time of 0.1 s. The capillary needle voltage was 3kV and the source temperature was maintained at 140°C . Nitrogen was used as the nebulizer gas. Cone voltage was 10 V for positive ionzation mode and 20 V for negative ionization mode. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
LCMS conditions 2 Speed analysis
The HPLC gradient was supplied by a Waters Alliance 2690 system with a columnheater set at 50°C. Flow from the column was split to a Waters 996 photodiode array (PDA) detector and a Waters-Micromass ZQ mass spectrometer with an electrospray ionization source operated in positive and negative ionization mode.
Reversed phase HPLC was carried out on a Xterra MS Cl 8 column (2.5 μm, 4.6 x 20 mm) with a flow rate of 3 ml/min. Three mobile phases (mobile phase A 95% 25mM ammoniumacetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 50% B and 50% C in 0.9 min., to 100 % B in 0.37 min, 100% B for 0.18 min. and reequilibrate with 100 % A for 0.2 min. An injection volume of 2 μL was used.
Mass spectra were acquired by scanning from 100 to 1000 in Is using a dweU time of 0.1 s. The capillary needle voltage was 3kV and the source temperature was maintained at 140°C . Nitrogen was used a the nebulizer gas. Cone voltage was 10 V for positive ionzation mode and 20 V for negative ionization mode. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
Table 4 : LCMS parent peak ([M ] defines the mass of the compound) and retention time (minutes
Figure imgf000072_0001
Figure imgf000073_0001
[M"] defines the mass of the compound * mass of the corresponding base
D. Pharmacological example
Inhibition of MCP-1 induced Ca-flux in human THP-1 cells MCP-1 binding to the CCR2 receptor induces a rapid and transient intracellular release of Ca2+ (secondary messenger) in several cell lines (Charo et al, PNAS 1994). Free Ca2+ levels can be measured using a Ca2+ sensitive dye. When the CCR2 receptor is blocked with a CCR2 receptor antagonist, the MCP-1 induced release of Ca2+ is inhibited.
Human THP-1 cells (monocytic cell line, ATCC TIB-202) were cultured in RPMI 1640 medium supplemented with 10 % fetal calf serum (FCS), 1% L-Glulamine, penicillin (50 U/ml) and streptomycin (50 μg/ml) (all GIBCO BRL, Gent). After centrifugation, cells were loaded for 30 minutes with the Ca2+ sensitive fluorescent dye Fluo-3 AM (Molecular Probes, Leiden, Netherlands) (2 milUon cells/ml in RPMI medium containing 4 μM Fluo-3 AM, 20 mM HEPES, 0.1 % Bovine Serum Albumin (BSA) and 5 mM probenecid). Excess dye was removed by 3 -fold washing with buffer (5 mM HEPES, 140 mM NaCl, 1 mM MgCl2, 5 mM KCl, 10 mM glucose, 2.5 mM probenecid 1.25 mM CaCl2, 0.1 % BSA; all further incubations were done in this buffer). Cells were plated at a density of 150 000 cells/well in dark- wall 96-well plates (Costar, Cambridge, MA) and sedimented by centrifugation (1 minute). The cells were pre-incubated for 20 minutes with test compound Then, 10"7 M hMCP-1 (Bachem, Bubendorf, Switserland) was added. Changes in intraceUular free Ca2+ concentration were measured using the Fluorescent Imaging Plate Reader (FLEPR, Molecular Devices, Munchen, Germany). Fluorescence was recorded every second from 10 seconds before the addition of the MCP-1 till 2 minutes after the addition (first minute: 60 records with 1 second intervals, second minute 20 records with 3 second intervals). The maximal fluorescence obtained during this time frame was used for further calculations.
Table 5 reports ρIC5o values obtained in the above-described test for compounds of formula (I). pICso defines -log IC50 wherein IC50 is the molar concentration of the test compound which inhibits 50 % of specific MCP-1 induced Ca2+ flux.
Table 5
Figure imgf000074_0001
Figure imgf000075_0001
Radioligand binding assay.
125 I-MCP-1 binding assays were performed in 96:well plates with 40 μg of protein per well. Compounds were dissolved and diluted in DMSO to 100X dilutions. A 10X concentration range of compounds was prepared in binding buffer (10% DSMO). Competition binding assays contained the following components in a total volume of 250 μl: 25 μl of the appropriate compound dilution (final concentration of 1% DMSO), 200 μl membranes from CCR2B- transfected CHO cells dissolved in binding buffer and 25 μl 12 I-MCP-1 (Bolton and Hunter labeled Amersham, specific activity = 2000 Ci/mmol, 0.15 nM final). Binding buffer was composed of 25 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 0.5% protease-free bovine serum albumin, pH 7.4. After 90 minutes incubation at 25 °C, membranes were harvested on GF/B filters - presoaked in 0.5% polyethylenimine, foUowed by washing with buffer containing 25 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 5 mM NaCl, pH 7.4. Filter bound radioactivity was determined by liquid scintillation counting. EC50 values (μM) and K values (μM) were calculated. The EC50 value indicates the concentration of the test compound that competes with MCP-1 for half of the specific binding sites; the value indicates the equilibrium dissociation constant, i.e. the concentration of the test compound that will bind to half of the binding sites at equilibrium in the absence of radioligand or other competitors. EC50 values and Kj values were calculated using non-linear regression in Graphpad Prism. Prism calculates the Kj or affinity of the receptor for the competing drug using the equation of Cheng and Prusoff (Biochem. Pharmacol. 1973, 22: 3099- 3108). A low Kj indicates a high affinity of the receptor for the test compound. EC.
K; = 50 [radioligand] 1 + KA wherein I describes the affinity of the radioligand for the receptor, i.e. the concentration of the radioligand that will bind to half of the binding sites at equilibrium in the absence of competitors.
Table 6 lists K values (μM) obtained in the above-described test for compounds of formula (I).
Table 6
Figure imgf000076_0001
Chemotactic response
The CCR2 antagonistic activity of the compounds of the present invention can also be determined by measuring the effect of the compounds on the chemotactic response of cells in the presence of a chemokine, such as for example MCP-1.
Mononuclear cells from human heparinized peripheral blood (PBMC) were isolated using Ficoll-Paque gradient centrifugation (Amersham Biosciences). Assays of chemotactic responsiveness were performed using disposable 96-well chemotaxis chambers (ChemoTx, Neuro Probe) with 5-μm pore size polycarbonate (PVP-free) filter membranes. Mononuclear cells were fluorescently labeled with 5 μg/ml Calcein- AM (Molecular Probes, Eugene, OR) at 37°C for 30 minutes. Labeled cells were washed twice and resuspended at 5xl06 cells/ml in Hanks' Balanced Salt Solution (Gibco BRL) supplemented with 0.2% bovine serum albumin. Subsequently, cells were pre-incubated for 10 minutes at room temperature with serial dilutions of the compounds in DMSO (dimethylsulfoxide) (final DMSO concentration of 0.2%). Bottom wells of the chemotaxis chamber were loaded with 28 μl medium containing 30 ng/ml recombinant hMCP-1 (R&D) or buffer only. Pre-treated cells (100.000 cells) were added in triplicate to the topside of the filter (20 μl) and incubated at 37°C in humidified air containing 5% C02. After 105 minutes incubation, the non-migrated cells were removed from the top of the filter by gently wiping the filter with a tissue. The migrated cells were measured using a fluorescent plate reader ( gitation = 485 nm; emisskm = 538 nm). The chemotactic response can be expressed as chemotactic index (CL), being the ratio of the means of migrated cells in the presence of MCP-1 and the means of migrated cells in the absence of chemokine. Percentage inhibition was calculated using the formula: F %inhibition = (1 - sample -F buffer )x\0Q ^U P-λ ~ f buffer with Fsampie, the fluorescence of the ceUs pre-incubated with 10, 1, 0.1, 0.01 or 0.001 μM compound and migrated to 30 ng/ml MCP-1 in the bottom wells; FMCP- the fluorescence of the cells pre-incubated with buffer-0.2% DMSO and migrated to 30 ng/ml MCP-1 and Fb r, the fluorescence of cells pre-incubated with buffer-0.2% DMSO and spontaneous migrated to buffer in the bottom wells. Table 7 lists the IC50 values (μM) obtained in the above-described test for compounds of formula (I). Assays were run in triplicate and repeated 2-7 times.
Table 7
Figure imgf000077_0001

Claims

Claims
1. A compound of formula
Figure imgf000078_0001
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof, wherein Ri represents hydrogen, Cι_6alkyl, C3-7cycloalkyl,
Figure imgf000078_0002
di(C gall y lJaminoQ-ealkyl, aryl or heteroaryl; each R2 independently represents halo,
Figure imgf000078_0003
Ci-βalkylthio, polyhaloCi-δalkyl, polyhaloCi-salkyloxy, cyano, aminocarbonyl, amino, mono- or
Figure imgf000078_0004
nitro, aryl or aryloxy; R3 represents hydrogen, cyano, Chalky 1 optionally substituted with hydroxy or
Figure imgf000078_0005
C(=0)-R7; R4 represents hydrogen or Ci-βalkyl; R5 represents hydrogen,
Figure imgf000078_0006
C2_6alkenyl, C2-6alkynyl, polyhaloCi-βalkyl, Ci-βalkyloxyd-βalkyl, aminoCi-όalkyl, mono-or di(Cι-4alkyl)aminoCι-6alkyl, aminocarbonylCι-6alkyl, mono-or di(C alkyl)aminocarbonylCι.6aIkyl or aryl; Rδa and
Figure imgf000078_0007
amino, mono-or di(Cι-<ιalkyl)amino, arylNH-, aminoCi-βalkyl, mono-or
Figure imgf000078_0009
ammocarbonylami
Figure imgf000078_0008
carbonylamino orhydroxyCi_6alkyl; or Rβa and Rg taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or piperazinyl substituted with Ci .galkyl; R7 represents hydrogen, Chalky!,
Figure imgf000078_0010
C2_6alkenyl, C2-6alkynyl, polyhaloCi-βalkyl, Ci-βalkyloxyCi-δalkyl, aminoCi-ealkyl, mono-or
Figure imgf000078_0011
di(Cι^alkyl)aminocarbonylCι-6alkyl, aryl or heteroaryl; Z represents a cyclic ring system selected from
Figure imgf000079_0001
(a-1) (a-2) (a-3) (a-4) (a-5) (a-*)
Figure imgf000079_0002
(a-7) (a-8) (a-9) (a-10) (a-11) (a-12)
Figure imgf000079_0003
(a-1 ) (a-16)
Figure imgf000079_0004
(a-18) each Rg independently represents hydrogen, halo, Ci-βalkyl, Ci-βalkyloxy,
Figure imgf000079_0005
polyhaloCi-salkyloxy, cyano, aminocarbonyl, mono-or
Figure imgf000079_0006
amino, mono-or di(Cι-4alkyl)amino, hydroxyCi-ealkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, morpholinyl, piperazinyl or nitro; each R9 independently represents hydrogen, halo or Ci-βalkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci-ealkyl, Ci-βalkyloxy, polyhaloCi-galkyl,
Figure imgf000079_0007
cyano, aminocarbonyl, mono-or
Figure imgf000079_0008
amino, mono-or di(Cι-4alkyl)amino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyL pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo,
Figure imgf000080_0001
polyhaloCi-βalkyl, polyhaloCi-βalkyloxy, cyano, aminocarbonyl, mono-or di(Cι-4alkyl)aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino or nitro; provided that l-(3,4-dimethoxybenzyl)-4-phenyl-lH-imidazole-2-thiol; and l-(o-chlorobenzyl)-5-e yl-4-phenyl-irmdazole-2-thiol are not included.
2. A compound according to claim 1 wherein R2 represents halo, C^alkyl, Ci-βalkyloxy or
Figure imgf000080_0002
3. A compound according to claim 2 wherein R2 represents halo or polyhaloCι-6alkyl.
4. A compound according to claim 3 wherein R2 represents halo.
5. A compound according to claim 4 wherein R2 represents fluoro.
6. A compound according to any one of the preceding claims wherein n is 2 or 3.
7. A compound according to claim 6 wherein n is 2.
8. A compound according to claim 7 wherein n is 2 and said two R2 substituents are placed in meta and para postion.
9. A compound according to any of one of the preceding claims wherein Z represents a radical of formula (a-1), (a-2), (a-3), (a-9), (a-10), (a-12), (a-13), (a-14) or (a-16).
10. A compound according to claim 9 wherein Z represents a radical of formula (a-1), (a-2), (a-9), (a-10) or (a-13).
11. A compound according to claim 10 wherein Z represents a radical of formula (a-9).
12. A compound according to any one of the preceding claims wherein R3 represents hydrogen, cyano, C(=0)-0-R5,
Figure imgf000080_0003
or C(=0)-R7.
13. A compound according to claim 12 wherein R3 represents cyano, C(=0)-0-R5,
Figure imgf000080_0004
14. A compound according to claim 13 wherein R3 represents C(=0)-0-Rs.
15. A compound according to claim 14 wherein R3 represents methoxycarbonyl.
16. A compound according to any one of the preceding claims wherein Rj represents Ci-δalkyl or Ci-ealkyloxyalkyl.
17. A compound according to claim 16 wherein Ri represents
Figure imgf000081_0001
18. A compound according to claim 17 wherein Ri represents ethyl.
19. A compound according to any one of the preceding claims wherein R» represents hydrogen.
20. A compound according to claim 1 or 2 wherein Rj represents
Figure imgf000081_0002
or Cι-6alkyloxyalkyl; R2 represents halo; R3 represents hydrogen, cyano, C(=0)-0-Rs, C(=0)-NR6aR6b, C(=0)-R7; Z represents a ring system selected from (a-1), (a-2), (a-3), (a-9), (a-10), (a-12), (a-13), (a-14) or (a-16); R represents hydrogen; n is 2.
21. A compound according to any one of the preceding claims wherein the compound is stereochemically pure.
22. A compound according to any one of the preceding claims wherein the compound has the following formula
Figure imgf000081_0003
23. A compound according to claim 1 wherein the compound has the following formula
Figure imgf000081_0004
Figure imgf000082_0002
Figure imgf000082_0001
Figure imgf000082_0003
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a polymoφhic form thereof.
24. A compound according to claim 1 wherein the compound is (S)-3-[l-(3,4-difluoro- phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-lH-imidazole-4-carboxylic acid methyl ester, a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a polymoφhic form thereof.
25. A compound according to claim 24 wherein the compound is (S)-3-[l-(3,4- difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dmydro-lH-imidazole-4- carboxylic acid methyl ester or a N-oxide thereof.
26. A compound according to claim 24 wherein the compound is (S)-3-[l-(3,4- difluoro-phenyl)-proρyl]-5-isoxazol-5-yl-2-thioxo-2,3-dmydro-lH-imidazole-4- carboxylic acid methyl ester or a pharmaceutically acceptable addition salt thereof.
27. A compound according to claim 24 wherein the compound is (S)-3-[l -(3,4- difluoro-phenyl)-ρropyl]-5-isoxazol-5-yl-2-thioxo-2,3-dmydro-lH-irrύdazole-4- carboxylic acid methyl ester or a quaternary amine thereof.
28. A compound according to claim 24 wherein the compound is (S)-3-[l-(3,4- difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-d ydro-lH-imidazole-4- carboxylic acid methyl ester.
29. A compound according to claim 24 wherein the compound is (S)-3-[l-(3,4- difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dmydro-lH-imidazole-4- carboxyUc acid methyl ester with a melting point of 128.5°C.
30. A compound as claimed in any one of the preceding claims for use as a medicine.
31. Use of a compound for the manufacture of a medicament for preventing or treating
Figure imgf000083_0001
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine, a polymoφhic form or a stereochemically isomeric form thereof, wherein Ri represents hydrogen, Ci-ealkyl, C3-7cycloalkyl, Ci-ealkyloxyCi-βalkyl, di Ci-ealkylJaminoCi-ealkyl, aryl or heteroaryl; each R2 independently represents halo, Cj-βalkyl, Ci-βalkyloxy, Ci-βalkylthio,
Figure imgf000083_0002
polyhaloCi-salkyloxy, cyano, aminocarbonyl, amino, mono- or di(Cι-4alkyl)amino, nitro, aryl or aryloxy; R3 represents hydrogen, cyano, Ci-βalkyl optionally substituted with hydroxy or
Figure imgf000083_0003
C(=S)-NR6aRsb,
Figure imgf000083_0004
or C(=0)-R7; R4 represents hydrogen or C-βalkyl; R5 represents hydrogen,
Figure imgf000083_0005
polyhaloCi-βalkyl, Ci-δalkyloxyCi-ealkyl, aminoCi-ealkyl, mono-or
Figure imgf000083_0006
aminocarbonylCi-βalkyl, mono-or di(Cι_4aϊkyl)aminocarbonylCι-6alkyl or aryl; R$a and R«, each independently represent hydrogen,
Figure imgf000083_0007
amino, mono-or
Figure imgf000083_0008
arylNΗ-,
Figure imgf000083_0009
mono-or di(Cι-4alkyl)amino
Figure imgf000084_0001
aminocarbonylamino,
Figure imgf000084_0002
carbonylamino or hydroxyCi-ealkyl; or R^a and Rδb taken together with the nitrogen to which they are attached form pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, moφholinyl, thiomoφholinyl or piperazinyl substituted with Ci-βalkyl; R7 represents hydrogen, C^aUcyl, hydroxyCj-6alkyL C2-6alkenyl, C2-6alkynyl,
Figure imgf000084_0003
Ci-βalkyloxyCi-βalkyl, aminoCi-βalkyl, mono-or
Figure imgf000084_0004
aminocarbonylCi-δalkyl, mono-or di^i^alkylJaminocarbonylCi^alkyl, aryl or heteroaryl; Z repre
Figure imgf000084_0005
Figure imgf000084_0006
(a-1) (a-2) (a-3) (a-4) (a-5) (a-6)
Figure imgf000084_0007
(a-7) (a-8) (a-9) (a-10) (a-11) (a-12)
Figure imgf000084_0008
(a-18) each Rg independently represents hydrogen, halo, Ci-βalkyl, Cι-6alkyloxy, polyhaloCi-βalkyl,
Figure imgf000084_0009
cyano, aminocarbonyl, mono-or di(C1- alkyl)aminocarbonyl, amino, mono-or di(Cι-4alkyl)amino, hydroxyCϊ-ealkylamino, aryl, aryloxy, piperidinyl, piperidinylamino, moφholinyl, piperazinyl or nhro; each R9 independently represents hydrogen, halo or d-βalkyl; n is 1, 2, 3, 4 or 5; aryl represents phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, Ci-salkyl, Q-salkyloxy, polyhaloCi-δalkyl, polyhaloC1-6alkyloxy, cyano, aminocarbonyl, mono-or
Figure imgf000085_0001
amino, mono-or di(Ci-4alkyl)amino, phenyloxy or nitro; heteroaryl represents furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isofhiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, each of said heterocycles optionally being substituted with one or two substituents each independently selected from halo, Cι- alkyL d-δalkyloxy, polyhaloCi-βalkyl, polyhaloCi-όalkyloxy, cyano, aminocarbonyl, mono-or
Figure imgf000085_0002
amino, mono-or di(Cι-4alkyl)amino or nitro. ►
32. Use of a compound as claimed in any one of claims 1 to 29 for the manufacture of a medicament for preventing or treating diseases mediated through activation of the CCR2 receptor.
33. Use according to claim 31 or 32 wherein the disease is an inflammatory disease.
34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 29.
35. A process of preparing a composition as claimed in claim 34 characterized in that a pharmaceuticaUy acceptable carrier is intimately mixed with a therapeuticaUy effective amount of a compound as claimed in any one of claims 1 to 29.
36. A process of preparing a compound as defined in claim 1 characterized by a) by reacting an intermediate of formula (Il-a) or (H-b) with KSCN in the presence of a suitable acid and a suitable solvent,
Figure imgf000086_0001
(π-b) with Ri, R2, Rt, Z and n as defined in claim 1; b) reacting an intermediate of formula (IH) with an intermediate of formula (TV) wherein Wi represents a suitable leaving group, in the presence of KSCN, a suitable acid a suitable solvent, and a suitable base,
Figure imgf000086_0002
(IV) (I-b) (m) with Ri, R2, R4, Z and n as defined in claim 1 and with R3- representing R3 other than hydrogen; c) reacting an intermediate of formula (V) with a suitable base in the presence of a suitable solvent
Figure imgf000087_0001
(V) with Ri, R2, Rt, Z and n as defined in claim 1 and with R3- representing R3 other than hydrogen; d) reacting an intermediate of formula (VT) with phosphoric trichloride or Burgess 'reagent optionally in the presence of a suitable solvent
Figure imgf000087_0002
(VT) with Rj, R2, R3, Rt, Rg and n as defined in claim 1 ; e) reacting an intermediate of formula (VET), wherein W2 represents a suitable leaving group, with an appropriate alcohol of formula HO-Rs- wherein R5' represents Ci-βalkyl or
Figure imgf000087_0003
in the presence of a suitable solvent
Figure imgf000087_0004
with R;, R2, R4, Z and n as defined in claim 1 ; f) reacting an intermediate of formula (VET), wherein W2 represents a suitable leaving group, with an intermediate of formula (VEfi) in the presence of a suitable solvent
Figure imgf000088_0001
with Ri, R2, Rt, Rόa, Rβb, Z and n as defined in claim 1 ; g) reacting an intermediate of formula (VII) with a suitable reducing agent in the presence of a suitable solvent
Figure imgf000088_0002
(vπ) (i-i) with Rj , R2, R*, Z and n as defined in claim 1 ; or, if desired converting compounds of formula (I) into each other following art- known transformations, and further, if desired converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid or into a therapeuticaUy active non-toxic base addition salt by treatment with a base, or conversely, converting the acid addition salt form into the free base by treatment with alkali, or converting the base addition salt into the free acid by treatment with acid; and if desired preparing stereochemically isomeric forms, quaternary amines or N-oxide forms thereof.
37. A process of preparing a compound as defined in claim 22 characterized by performing the reactions according to claim 36 starting from an intermediate wherein the carbon atom carrying the Ri and Rt substituent has the (S) configuration.
38. A compound of formula (EX-b-l-l)
Figure imgf000089_0001
(IX-b-1 -1) a N-oxide, a pharmaceutically acceptable addition salt or a quaternary amine thereof, wherein Alk represents methyl, ethyl or n-propyl, and each R2a and R2b independently represents chloro, fluoro or trifluoromethyl provided that when R2a and R2 are both chloro, then Alk is other than ethyl.
39. A compound according to claim 38 wherein the compound is
Figure imgf000089_0002
lø (LX-b-1-l-a)
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